Flow governors for use in medicinal inhalers

ABSTRACT

A flow governor for use in a medicinal inhaler. The flow governor can include (i) a tubular element that defines at least a portion of an air flow path, the tubular element comprising at least one flexible wall configured to flex inwardly in response to an air flow in the air flow path; and (ii) an internal support structure, located within the tubular element and configured to preserve at least a predetermined cross-sectional area of the air flow path within the tubular element when the at least one flexible wall of the tubular element flexes inwardly.

FIELD

The present disclosure generally relates to flow governors for use inmedicinal inhalers, and flow governor assemblies and medicinal inhalerscomprising the flow governors.

BACKGROUND

Delivery of aerosolized medicament to the respiratory tract for thetreatment of respiratory and other diseases is conventionally done usinginhalers of either the pressurised metered dose inhaler (pMDI), the drypowder inhaler (DPI) or the nebulizer type. pMDI inhalers in particularhave become an industry standard, and are familiar to many patients whosuffer from either asthma or from chronic obstructive pulmonary disease(COPD). Conventional pMDI devices comprise an aluminum canister, sealedwith a metering valve, which contains the medicament formulation.Generally, the medicament formulation is a pressurized formulationcontaining either fine particles of one or more medicinal compoundssuspended in a liquefied hydrofluoroalkane (HFA) propellant, or asolution of one or more medicinal compounds dissolved in apropellant/co-solvent system. Formulations incorporating one drug insolution and another one in suspension form are also known.

In a conventional pulmonary pMDI, the sealed canister is provided to thepatient in an actuator. The actuator is conventionally a generallyL-shaped plastic molding comprising a generally cylindrical verticaltube that surrounds the canister plus a generally horizontal tube thatforms a patient port (e.g., a mouthpiece or nosepiece) that defines aninspiration orifice. To use such an inhaler, the patient exhales, placesthe patient port in a body cavity (e.g., mouth or nose) and then inhalesto draw air through the inspiration orifice. (In the case of nasalpMDIs, it is not always necessary to inhale.) The majority of suchinhalers are of the pulmonary “press-and-breathe” type, where thepatient must press down on the protruding end of the canister in orderto operate the metering valve to release a metered dose of medicamentfrom the canister into the inhaled air stream and thence through themouthpiece into their lungs. This requires a significant degree ofcoordination of timing of inhalation and dose release if the emergingcloud of aerosolized medicament is to be taken far enough into the lungsto provide maximum therapeutic benefit. If the patient releases the dosebefore inspiratory flow has been established, then a proportion of thedrug is likely to be lost in the mouthpiece or the patient's mouth.Conversely, if released much after the start of inhalation, then thedeeper regions of the lungs might already be full of air and notpenetrated by the following bolus of released medicament aerosol.

To overcome what can be quite a challenge for some patients, pMDI devicedesigns have been created that employ automatic breath-actuatedtriggering, releasing a dose only in response to the patient's inhaledbreath. The AUTOHALER™ metered dose inhaler, available from 3M Company,St. Paul, Minn., and the EASIBREATHE™ inhaler, available from TevaPharmaceutical Industries Ltd., Israel, are two such pMDI devices thatuse breath-actuation to attempt to better coordinate dose release withinhalation.

SUMMARY

Even though breath-actuated inhalers can be a useful aid in achievingcoordination between inhalation and medicament dose release, withconsequently improved medicament delivery to many patients' lungs, thesedevices are however unable to overcome all the potential weaknesses thatpatients can exhibit in their inhaler use technique. For example, evenif patients can achieve good timing of dose release, whether viabreath-actuation or simply via good press-and-breathe coordination, theycan have a tendency to inhale at sub-optimal flow rates. For example,very high inspiratory flow rates (i.e., volumetric flow rates) can giverise to excessive and problematic drug deposition on the back of thethroat, while very low inspiratory flow rates can lead to poorentrainment of the aerosolized medicament spray. A related additionalpotential problem is that very high inspiratory flow rates can lead tomore rapid filling of the lungs and consequently an even greater needfor good coordination.

As a result of poor inhalation and dose release coordination, manypatients do not get the full therapeutic benefit of their medicinalinhalers. For example, many patients with uncontrolled asthma are unableto (i) achieve a flow rate between 10 to 50 liters/minute (L/min.); (ii)maintain the flow rate for at least 1.5 seconds; and (iii) hold theirbreath for at least 5 seconds after inspiration. Poor inhaler usetechnique has been found to correlate to poor control of asthma. Similarconsiderations probably apply to other respiratory diseases treatedusing inhaled medication, e.g. to COPD.

The general view in the guidance provided by pharmaceutical companies isthat pMDI medications should be taken with patients taking a slow anddeep inhalation, normally interpreted as being less than 50-60 L/min.

For conventional pMDIs and other inhalers, however, the inhalation flowrate can be poorly controlled from one user to another and even from onebreath to another for the same patient. Some patients can sometimesachieve flow rates as high as 250 L/min., while others can sometimesachieve an order of magnitude less Inhaling the medicament at a lowerflow rate tends to reduce drug impaction in the upper airways andincreases drug deposition deeper in the lung. If a patient is unable tocontrol their asthma, or any other respiratory disease requiring use ofan inhaler, this will impact their quality of life and may lead to therequirement for further medical intervention.

Spacer devices have previously been devised which fit onto themouthpiece of a pMDI in order to reduce the velocity of the emergentplume of medicament aerosol and to provide a volume in which it canexpand and its propellant can evaporate more completely. This serves toavoid some of the problems of coordination and also avoids the tendencyfor high throat deposition caused by excessively fast drug particleinhalation. However, spacer devices are very bulky, and they can retainan excessive proportion of the drug on their walls, thereby reducing thedose that reaches the patient. Spacer devices can also be highlysensitive to electrostatic charge, which can often be strongly affectedby the way in which they are washed or dried.

Because the manner in which patients inhale through their pMDIs is animportant determinant of the delivery of drug to their lungs andtherefore of the benefits they obtain from their medication, the presentinventors sought to control the inhalation profile.

A further difficulty arises in getting all patients to inhale in asimilar and consistent manner. Inhaler designs each have their owninherent resistance (R) to air flow. This is often expressed in theunits (Pa)^(0.5)(min./L), and is related to inhalation air flow rate(FR) and patient-created pressure drop (PD) by the equation:

R=PD^(0.5)/FR.

Existing pMDI inhalers usually have low inherent resistances to airflow, for example below 0.5 Pa^(0.5) min./L, which makes it difficultfor patients to control their inhalation flowrate.

Breathing profiles can be too rapid. Breath-dosing coordination can bedifficult under such circumstances, and both the inter-patient andintra-patient variability can be high. With resistances of this order itcan also be difficult for patients to achieve a steady flow rate of aduration of more than perhaps 2 to 2.5 seconds. Flow rate consistencyduring an inspiratory maneuver, and between inhalations, can bedifficult to obtain. For example, flow rate ‘spikes’ can occur, wherebypatients achieve fairly high but very transient flow rates. This canlead to poor spatial distributions of drug in their airways.

However, adding a significant fixed (‘static’) resistance to the designof a pMDI device also poses problems. By restricting the geometry of theair flow path in an inhaler, much higher resistances could be created,for example 1.6 Pa^(0.5) min./L or more. Such resistances are typical ofsome DPI devices, where a high resistance is required to generate theenergy needed to disperse and/or de-agglomerate a dose of medicamentpowder from a system without the energy content of a liquefiedpropellant. Unfortunately, though, while high resistances make it mucheasier for many patients to inhale more slowly and steadily through aninhaler, and for a longer period (e.g. 5 seconds or more), they pose anobstacle to some weaker patients who struggle to inhale adequate amountsof air against such a resistance. COPD patients, in particular, oftenfind it difficult to inhale through such high resistances because oftheir impaired lung function.

In order to overcome some of the above-described issues related toeither a low or a high inhaler resistance, while also avoiding the needfor a spacer device, the present inventors developed the flow governorsof the present disclosure, which have the ability to change theirgeometry and resistance to air flow as a function of pressure dropexperienced, i.e., between an inlet and outlet of the flow governor.Flow governors of the present disclosure (which can also be referred toas “flow rate limiters,” “flow limiters,” “flow regulators,” “flowlimitation devices,” or derivations thereof) allow appreciable air flowrates at low differential pressures, while increasing air flowresistance at higher differential pressures in order to limit the airflow rates to values more consistent with those obtained at lowerdifferential pressures to reduce inter-patient and intra-patientinhalation variability.

Some aspects of the present disclosure provide a flow governor for usein a medicinal inhaler. The flow governor can include (i) a tubularelement that defines at least a portion of an air flow path, the tubularelement comprising at least one flexible wall configured to flexinwardly in response to an air flow in the air flow path; and (ii) aninternal support structure, located within the tubular element andconfigured to preserve at least a predetermined cross-sectional area ofthe air flow path within the tubular element when the at least oneflexible wall of the tubular element flexes inwardly.

Other features and aspects of the present disclosure will becomeapparent by consideration of the detailed description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side cross-sectional view of a conventional pressurizedmetered dose inhaler (pMDI).

FIG. 2 is a graph schematically illustrating flow rate (L/min.) versustime (seconds) of inhalation flow profiles of COPD patients usingconventional medicinal inhalers and using medicinal inhalers comprisinga flow governor of the present disclosure.

FIG. 3 is an isometric view of a flow governor according to oneembodiment of the present disclosure, shown at rest.

FIG. 4 is a front longitudinal cross-sectional view of the flow governorof FIG. 3, taken along line 4-4 of FIG. 3, shown at rest.

FIG. 5 is a transverse cross-sectional view of the flow governor ofFIGS. 3 and 4, taken alone line 5-5 of FIG. 3, shown at rest.

FIG. 6 is a side longitudinal cross-sectional view of the flow governorof FIGS. 3-5, taken along line 6-6 of FIG. 3, shown at rest.

FIG. 7 is a transverse cross-sectional view of the flow governor ofFIGS. 3-6, taken along line 5-5 of FIG. 3, shown in operation.

FIG. 8 is a side longitudinal cross-sectional view of the flow governorof FIGS. 3-7, taken along line 6-6 of FIG. 3, shown in operation.

FIG. 9 is a front longitudinal cross-sectional view of a flow governoraccording to another embodiment of the present disclosure, shown atrest.

FIG. 10 is a transverse cross-sectional view of the flow governor ofFIG. 9, shown at rest.

FIG. 11 is a side longitudinal cross-sectional view of the flow governorof FIGS. 9-10, shown at rest.

FIG. 12 is a transverse cross-sectional view of the flow governor ofFIGS. 9-11, shown in operation.

FIG. 13 is a side longitudinal cross-sectional view of the flow governorof FIGS. 9-12, shown in operation.

FIG. 14 is a front longitudinal cross-sectional view of a flow governoraccording to another embodiment of the present disclosure.

FIG. 15 is a side cross-sectional view of a medicinal inhaler accordingto one embodiment of the present disclosure, comprising the flowgovernor of FIGS. 3-8 located in a dedicated air flow path and a coverover an open end of a housing that receives a medicament canister.

FIG. 16 is a side cross-sectional view of a medicinal inhaler accordingto another embodiment of the present disclosure, comprising the flowgovernor of FIGS. 3-8 located in a dedicated air flow path and a skirtseal located between a medicament canister and a housing that receivesthe canister.

FIG. 17 is a side cross-sectional view of a medicinal inhaler accordingto another embodiment of the present disclosure, comprising the flowgovernor of FIGS. 3-8 located in a cap configured to be coupled to anopen end of a housing that receives a medicament canister.

FIG. 18 is a side cross-sectional view of a medicinal inhaler accordingto another embodiment of the present disclosure, comprising the flowgovernor of FIGS. 3-8 located in a dedicated air flow path and one ormore pressure sensors in fluid communication with the dedicated air flowpath.

FIG. 19 is a side cross-sectional view of a breath-actuated medicinalinhaler according to one embodiment of the present disclosure,comprising the flow governor of FIGS. 3-8 located in a dedicated airflow path.

FIG. 20 is a front longitudinal cross-sectional view of a flow governorassembly of a medicinal inhaler according to one embodiment of thepresent disclosure, comprising the flow governor of FIGS. 3-8, anupstream venturi, and one or more pressure sensors positioned in fluidcommunication with the flow governor.

FIG. 21 is an exploded isometric view of the flow governor assembly ofFIG. 20.

FIG. 22 is a side longitudinal cross-sectional view of a portion of aflow governor assembly of a medicinal inhaler according to anotherembodiment of the present disclosure, comprising a flow governoraccording to one embodiment of the present disclosure, shown at rest.

FIG. 23 is a front longitudinal cross-sectional view of a portion of aflow governor assembly of a medicinal inhaler according to anotherembodiment of the present disclosure, comprising a flow governoraccording to one embodiment of the present disclosure, shown at rest.

FIG. 24 is a graph of inhalation pressure drop (kPa) versus inhalationflow rate (L/min.) for three different embodiments of flow governors ofthe present disclosure.

FIG. 25 is a graph of inhalation pressure drop (kPa) versus inhalationflow rate (L/min.) for three further embodiments of flow governors ofthe present disclosure.

FIG. 26 is a front longitudinal cross-sectional view of a flow governoraccording to another embodiment of the present disclosure, shown atrest.

FIG. 27 is a transverse cross-sectional view of the cross member of theflow governor of FIG. 26.

FIGS. 28A and 28B are transverse cross-sectional views of alternativecross members of the flow governors of the present disclosure.

DETAILED DESCRIPTION

The present disclosure generally relates to a flow governor for use in amedicinal inhaler, the flow governor being adapted to change itsgeometry, and thereby its resistance to air flow, as a function ofpressure drop between its inlet and its outlet. The flow governors ofthe present disclosure therefore provide a means of governing the airflow rate (i.e., volumetric flow rate) through a medicinal inhaler toreduce inter-patient and intra-patient inhalation variability andprovide a more reproducible level of drug deposition in the lung. Suchflow governors can provide a variable (dynamic) resistance to air flowin an air flow path of a flow governor assembly and/or medicinalinhaler.

Use of an inhaler incorporating one or more flow governors of thepresent disclosure could provide significant benefits to a sufferer ofrespiratory or other inhalation-treated disease. Apart from consistencyof use and results, flow governors of the present disclosure can avoidthe need for bulky spacer devices that are intended to reduce the needfor such coordination. When used in conjunction with data recording offlow rates and other inhaler-use events and data, it can also improvephysician monitoring of chronically ill patients. When two or more flowgovernors of the present disclosure are employed in a flow governorassembly and/or a medicinal inhaler, the flow governors can be arrangedin parallel or in series.

Flow governors of the present disclosure can include (i) a tubularelement that defines at least a portion of an air flow path therewithin,the tubular element comprising one or more flexible walls configured toflex (or collapse) inwardly in response to an air flow in the air flowpath, and (ii) an internal support structure located within the tubularelement and configured (e.g., shaped, dimensioned, positioned and havingdesired material properties) to preserve at least a predeterminedcross-sectional area of the air flow path within the tubular elementwhen the one or more flexible walls of the tubular element are flexed(or collapsed) inwardly. As a result, part of the air flow pathcross-sectional area remains open even when the tubular element hascollapsed, in order to allow the continued inhalation of air and emittedmedicament. A “predetermined cross-sectional area of the air flow pathwithin the tubular element” can include a portion of the air flow paththat passes through the internal support structure, e.g., when theinternal support structure includes one or more hollow portions orcomponents, as well as a cross-sectional area of space between thetubular element and the internal support structure. The material makeupof the tubular element flexible walls can also be chosen to achieve thedesired cross-sectional area between the tubular element and theinternal support structure.

In some embodiments, calculation of the predetermined cross sectionalarea can be based on the flow resistance required to meet the governingrequirements, for example, rearranging the following equation to find‘A’:

R=sqrt[0.5*ρ*(f*l/d+k)]/A

where:

A=cross-sectional area (e.g., m²)

ρ=air density (e.g., kg/m³)

f=friction coefficient (dimensionless)

l=length of wall in in the flow direction (e.g., m)

d=tube diameter (e.g., m)

k=singular losses coefficient (dimensionless)

R=flow resistance (e.g., Pa^(0.5)*min./L)

Ensuring that the predetermined cross sectional area is maintained canbe achieved through use of the internal support structure whichphysically inhibits the tubular element from collapsing to a point wherethe cross sectional area is less than the predetermined cross sectionalarea, and may also include a suitable selection of the material makeupof the flexible walls of the tubular element.

At low inhalation flow rates, the patient experiences a low or moderatestatic resistance to air flow, but when the inhalation flow rate throughthe flow governor exceeds a certain flow rate, the tubular elementpartially collapses and thus imposes an additional resistance to airflow: the inhaler changes from being a low or medium resistance inhalerto a high resistance inhaler. That is, the flow governor providesvariable resistance to the assembly comprising the flow governor and/orthe inhaler comprising the flow governor (or flow governor assembly).

The present inventors discovered that it can be desirable to have acombination of a static medium resistance and a large variableresistance to make it easier for the patient to inhale with a specific(e.g., target) flow rate. There can be several contributors to thestatic resistance of a flow governor assembly (or inhaler), such asinlets, outlets, one or more constrictions, the flow governor, othergeometrical features of the air flow path, or combinations thereof. Asdescribed in greater detail below with respect to FIGS. 20-23, such aconstriction can include a venturi section, a narrow passageway, atortuous path, or a combination thereof. The constriction can be used toadd a desired amount of static resistance to the assembly (or inhaler),and can be separate and independent from the flow governor. For example,the constriction can be positioned (i) at a location in the housingupstream of the flow governor, and/or (ii) at a location in the housingdownstream of the flow governor, such that the constriction is outsideof and separate from the flow governor, i.e., to provide a known staticresistance in addition to the flow governor.

The present inventors have recognized that a critical consideration isthe balance of the static and variable resistances of a flow governorassembly (or inhaler) comprising a flow governor of the presentdisclosure, so that the flow governor assembly (or an inhaler comprisingthe flow governor assembly or the flow governor) can be used by a largeproportion of weaker (e.g., COPD) patients with a minimum ofinter-patient and intra-patient variability in inhalation flow rate. Forexample, as mentioned in the ‘Summary’ above, air flow resistance can becalculated according to the following equation:

R=PD^(0.5)/FR

where:

R=air flow resistance (e.g., Pa^(0.5)*(min./L)

PD=pressure drop (e.g., Pa)

FR=volumetric air flow rate (e.g., L/min.)

Particularly, the present inventors discovered that at low pressuredrops (e.g., 0.5 kPa), a flow governor assembly (or inhaler) having aproperly balanced static and dynamic air flow resistance can exhibit afirst overall air flow resistance R₁, based on the static resistance ofthe assembly (or inhaler) comprising the flow governor. At higherpressure drops (e.g., 4 kPa), the flow governor assembly (or inhaler)can exhibit a second air flow resistance R₂, predominantly based on therelatively large dynamic resistance provided by the flow governor. As aresult, the balance of static and dynamic resistances can exhibitappropriate overall air flow resistances at both low pressure drops andhigh pressure drops to achieve a target governing flow rate over a rangeof pressure drops.

In some embodiments, the ratio of R₂/R₁ (e.g., at a given volumetricflow rate, or to achieve a target governing volumetric flow rate) of aflow governor assembly (or inhaler) comprising the flow governor (andoptionally, further comprising a constriction to introduce a desiredlevel of static resistance) can be at least 1.2; in some embodiments, atleast 1.3; in some embodiments, at least 1.5; and in some embodiments,at least 2. In some embodiments, the ratio of R₂/R₁ (e.g., at a givenvolumetric flow rate, or to achieve a target governing volumetric flowrate) can be no greater than 3; in some embodiments, no greater than2.9; in some embodiments, no greater than 2.8; in some embodiments, nogreater than 2.7; in some embodiments, no greater than 2.5; and in someembodiments, no greater than 2.

In some embodiments, a flow governor assembly (or inhaler) comprisingthe flow governor can provide an overall resistance (e.g., R₁) to airflow of at least 0.4 Pa^(0.5)*min./L at a pressure drop (i.e., betweenan air inlet and an air outlet of the air flow path of the assembly (orinhaler)) of 0.5 kPa. In some embodiments, the overall resistance to airflow can be at least 0.5 Pa^(0.5)*min./L at 0.5 kPa; and in someembodiments, at least 0.6 Pa^(0.5)*min./L at 0.5 kPa. In someembodiments, the overall resistance can be no greater than 1.2Pa^(0.5)*min./L at 0.5 kPa; in some embodiments, no greater than 1.1Pa^(0.5)*min./L at 0.5 kPa; in some embodiments, no greater than 1.0Pa^(0.5)*min./L at 0.5 kPa; in some embodiments, no greater than 0.8Pa^(0.5)*min./L at 0.5 kPa; and in some embodiments, no greater than 0.7Pa^(0.5)*min./L at 0.5 kPa.

In some embodiments, the overall resistance (e.g., R₂) can be at least 1Pa^(0.5)*min./L at 4 kPa; in some embodiments, at least 1.1Pa^(0.5)*min./L at 4 kPa; in some embodiments, at least 1.2Pa^(0.5)*min./L at 4 kPa; and in some embodiments, at least 1.5Pa^(0.5)*min./L at 4 kPa. In some embodiments, the overall resistancecan be no greater than 3.2 Pa^(0.5)*min./L at 4 kPa; in someembodiments, no greater than 3 Pa^(0.5)*min./L at 4 kPa; in someembodiments, no greater than 2.5 Pa^(0.5)*min./L at 4 kPa; in someembodiments, no greater than 2.2 Pa^(0.5)*min./L at 4 kPa; in someembodiments, no greater than 2.0 Pa^(0.5)*min./L at 4 kPa; and in someembodiments, no greater than 1.8 Pa^(0.5)*min./L at 4 kPa.

In some embodiments, the overall resistance to air flow at low pressuredrops (e.g., 0.5 kPa), R₁, can range from about 1.1 to about 0.4Pa^(0.5)*min./L (e.g., to achieve a governing flow rate ranging fromabout 20 L/min. to about 60 L/min.); and in some embodiments, can rangefrom about 0.8 to about 0.6 Pa^(0.5)*min./L; and in some embodiments,can range from about 0.7 to about 0.5 Pa^(0.5)*min./L.

In some embodiments, the overall resistance to air flow at high pressuredrops (e.g., 4 kPa), R₂, can range from about 3.2 to about 1.0Pa^(0.5)*min./L (e.g., to achieve a governing flow rate ranging fromabout 20 L/min. to about 60 L/min.); and in some embodiments, can rangefrom about 2.5 to about 1.5 Pa^(0.5)*min./L; and in some embodiments,can range from about 2.3 to about 1.8 Pa^(0.5)*min./L.

The flow governors of the present disclosure are suitable for use inmultiple forms of inhalers for the delivery of doses of medicament inthe form of aerosols to the respiratory tract, including oral pulmonaryinhalers and nasal inhalers. Flow governors of the present disclosureare suitable for use in a variety of inhalers, including but not limitedto, one or more of a pressurized metered dose inhaler (pMDI) (e.g., apress-and-breathe pMDI, a mechanical (i.e., mechanically triggered)breath-actuated pMDI, an electronic (i.e., an electronically triggered)breath-actuated pMDI, or a combination thereof); a dry powder inhaler(e.g., a single dose (e.g., capsule) DPI, a multi-dose (e.g., tapebased, or reservoir based) DPI, or a combination thereof); a nebulizer(e.g., a pocket nebulizer); or a combination thereof.

GB Patent No. 2266466 discloses an exemplary electronically triggeredbreath-actuated pMDI that could be modified to incorporate a flowgovernor of the present disclosure. PCT Publication No. WO 2015/34709discloses an exemplary DPI that could be modified to incorporate a flowgovernor of the present disclosure. PCT Publication No. WO 92/12799discloses an exemplary pocket nebulizer that could be modified toincorporate a flow governor of the present disclosure. A flow governorof the present disclosure can be used in any of the inhalers disclosedin GB Patent No. 2266466, PCT Publication No. WO 2015/34709, PCTPublication No. WO 92/12799 (each of which is incorporated herein byreference in its entirety), or a combination thereof.

For example, some embodiments of the present disclosure provide amedicinal inhaler comprising a flow governor and a breath actuationmechanism. In some embodiments, the breath actuation mechanism can beconfigured to trigger to release a dose of medicament at an inspiratoryflow rate less than a governing flow rate of the flow governor.

Generally, it is important that the triggering flow rate is not set toolow, to avoid the risk that the breath-actuated inhaler might operateaccidentally or that it will deliver the medicament at too low aninhalation rate for adequate therapeutic effect. It is also importantthat the triggering flow rate is not set so high that a patient (e.g. aweak COPD patient) cannot achieve the triggering flow rate.

The triggering flow rate of the breath-actuation system needs to bebelow the governing air flow rate, in order that the latter does notprevent the triggering flow rate from being achieved. For example, insome embodiments, the target triggering flow rate of an inhaler can be15 liters/minute (L/min.) and the target governing flow rate can be 30L/min. In reality, a “target governing flow rate” may actually include arange of flow rates, as described in the Examples section with referenceto FIGS. 24 and 25, such that the target governing flow rate mayactually be a target range of flow rates. Manufacturing tolerances canbe maintained such that individual inhalers all have an actualtriggering flow rate of significantly less than their governing flowrate. Environmental factors such as temperature and atmospheric pressurewill also broaden the range of values actually obtained. For example,actual triggering flow rates might vary between 10 L/min. and 20 L/min.,and actual governing flow rates might vary between 25 L/min. and 35L/min.

Some embodiments of the present disclosure provide a medicinal inhalercomprising a flow governor and an inspiratory air flow detection (or“inspiratory flow rate detection system,” or “air flow detectionsystem,” or “flow rate detection system,” or derivations thereof) and/ormeasurement system. In some embodiments, such a detection system caninclude at least one pressure sensor located in the inhaler andconfigured to allow the inspiratory air flow rate to be sensed. Forexample, at least one pressure sensor can be located upstream of theflow governor in an air flow path of the medicinal inhaler. In someembodiments, such a detection system can include (i) a pressure sensorlocated in fluid communication with the air flow path, upstream of theflow governor, and (ii) a venturi constriction in the air flow pathlocated adjacent where the pressure sensor is in fluid communicationwith the air flow path. Such a venturi constriction can speed up thelocal air velocity to enhance the sensitivity of the pressure sensor,allowing for less sensitive, and less costly, sensors to be employed.Such a detection system can further include a second pressure sensorlocated in fluid communication with the air flow path, downstream of theflow governor, such that air flow direction can be determined, i.e., inorder to distinguish between inhalation and exhalation.

Some embodiments of the present disclosure provide a medicinal inhalercomprising a flow governor, a breath actuation mechanism, and aninspiratory air flow detection system.

In some embodiments of the present disclosure, the breath-actuationsystem can be an electronically triggered breath-actuation system. Forexample, the one or more pressure sensors can provide an electricalsignal which is used to trigger dose release according to a definedalgorithm. The dose release system may be a mechanical system, triggeredby the electronic system's algorithm. Optionally, the electronic systemmay be housed in a reusable module, in order to reduce the overall costof a prolonged period of treatment.

Additional details of flow governors and inspiratory air flow detectionsystems in combination with flow governors are described in U.S.Provisional Application No. 62/270,076, entitled “Flow governorassemblies for use in medicinal inhalers”, which is incorporated hereinby reference in its entirety.

Dose release firing systems that can be employed in combination withflow governors of the present disclosure are described in U.S.Provisional Application No. 62/270,066, entitled “Dose release firingsystems and medicinal inhalers comprising same” and U.S. ProvisionalApplication No. 62/270,081, entitled “Medicinal Inhalers”, each of whichis incorporated herein by reference in its entirety. In addition,auto-reset dose release firing systems that can be employed incombination with flow governors of the present disclosure are describedin U.S. Provisional Application No. 62/270,070, entitled “Auto-resetdose release firing systems, medicinal inhalers comprising same, andmethods of using same”, which is incorporated herein by reference in itsentirety.

Some firing systems (e.g., which can be used in combination with flowgovernors of the present disclosure) can produce a small time delaybetween the start of inhalation and the time when the medication isreleased. Desirably, medication release occurs within 0.5 sec of thestart of inhalation. A typical COPD patient has a tidal lung capacity ofabout 1.5 L. If the inhalation flow rate is limited by the flow governorto about 30 L/min., then the time of inhalation could be expected toextend to about 3-4 seconds. In reality, COPD patients may not be ableto inhale for this long, due to their poor lung function, but it isanticipated that there will be sufficient time for drug to betransferred to the lung.

Some embodiments of the present disclosure provide a method of treatmentof a pulmonary condition in a human patient, the method comprising: (i)providing a medicinal inhaler incorporating a flow governor comprisingthe tubular element and internal support structure described above; (ii)inserting a patient port of the medicinal inhaler into a body cavity(e.g., a mouth or nose); and (iii) actuating the medicinal inhaler whileinhaling.

In some embodiments, the present disclosure can provide a method ofusing a medicinal inhaler, or of treating a pulmonary condition, whichcan include providing a flow governor of the present disclosure in anair flow path of the medicinal inhaler, and varying an air flowresistance of the inhaler in response to air flow in the air flow pathof the flow governor. The method can further include inserting a patientport into a body cavity; and inhaling through the patient port to causeair flow in the air flow path of the flow governor. Varying the air flowresistance of the inhaler can include flexing one or more tubular wallsof a tubular element of the flow governor inwardly toward an internalsupport structure located within the tubular element, the internalsupport structure configured to preserve at least a predeterminedcross-sectional area of the air flow path within the tubular elementwhen the one or more tubular walls flexes inwardly.

Definitions

The terms “a”, “an”, and “the” are used interchangeably with “at leastone” to mean one or more of the elements being described.

The term “and/or” means either or both. For example “A and/or B” meansonly A, only B, or both A and B.

The terms “including,” “comprising,” or “having,” and variationsthereof, are meant to encompass the items listed thereafter andequivalents thereof as well as additional items.

Unless specified or limited otherwise, the terms “connected” and“coupled” and variations thereof are used broadly and encompass bothdirect and indirect connections and couplings.

Further, “connected” and “coupled” are not restricted to physical ormechanical connections or couplings.

The term “flexible” is used to refer to a material and/or structure thatcollapses or significantly deforms in response to an air pressuredifferential existing across the material and/or structure in itstypical mode of operation. The term ‘rigid’ is used to refer to amaterial and/or structure that does not collapse or significantly deformunder the forces it experiences in its typical mode of operation. Forexample, the tubular element of flow governors of the present disclosureis generally flexible and deformable in its normal operation, whereasthe internal support structure of flow governors of the presentdisclosure is generally rigid or non-deformable in its normal operation.

The term “tubular” is used to refer to a hollow structure having one ormore walls that define an open passageway therein. In some embodiments,the term “tubular” can more specifically refer to elongated hollowstructures. Tubular elements of flow governors of the present disclosureor tubular air flow paths of the present disclosure can have anycross-sectional shape desired (i.e., transverse cross-sectionalshape—taken substantially orthogonally with respect to a longitudinalaxis of the tubular structure), including, but not limited to, one ormore of circular, elliptical or oblong (i.e., having a longer major axisand a shorter minor axis), triangular, rectangular, square, trapezoidal,polygonal, star-shaped, D-shaped, other suitable cross-sectional shapes,or a combination thereof. In some embodiments, tubular structures of thepresent disclosure can have a circular cross-sectional shape.

The present disclosure will be described with respect to particularembodiments and with reference to certain drawings but the invention isnot limited thereto. The drawings described are only schematic and arenon-limiting. In the drawings, the size of some of the elements may forillustrative purposes be exaggerated and not drawn to scale. Identical,similar or equivalent features in different embodiments have beendenoted by similar numerals but with the addition to them of 100, 200,300, etc.

Before describing the embodiments in accordance with the presentinvention, a typical embodiment of a conventional pMDI device will bedescribed with reference to FIG. 1.

FIG. 1 illustrates a conventional pressurized metered dose inhaler(pMDI) 50 comprising a canister 51 containing a medicament formulation52, the canister comprising a can 53 sealed with a metering valve 54.The canister 51 sits within a housing (or “actuator”) 55 comprising atubular sleeve portion 56 having an open end 47 dimensioned to receivethe canister 51 and from which its base 49 can protrude, and a portionin the form of a patient port 57 (e.g., in the form of a mouthpiece)that defines an inspiration orifice (or an air outlet) 45. Such apatient port of an inhaler is sometimes referred to herein as a“mouthpiece” for simplicity. However, it should be understood that suchmouthpieces can instead be configured to be nosepieces of nasal inhalersand that the present disclosure can equally apply to nasal inhalers evenwhere not specifically mentioned herein. The open end 47 of the housing55 can define an aspiration orifice, or an air inlet, and the air outlet45 can define an inhalation orifice, or an air outlet.

A stem portion 58 protrudes from the metering valve 54 and is locatedand retained by friction in a stem socket 59 formed as an integral partof the housing 55. A spray orifice 60 is formed in the stem socket 59,and provides a passage for fluid communication between the valve stemportion 58 and the inspiration orifice 45. In use, a patient places thepatient port (e.g., mouthpiece) 57 into a body cavity (e.g., mouth) andthen inhales through it while at the same time pressing downwards on theprotruding base 49 of the canister 51. The pressing force serves to movethe canister 51 downwards relative to the valve's stem portion 58. Thatrelative movement serves to isolate a metered dose of medicamentformulation from the bulk formulation in the canister 51 and then todischarge it via a hollow bore 48 formed in the stem portion 58. Thedischarged dose then passes along the fluid passageway through the stemsocket 59 and the spray orifice 60 and emerges in the form of a finerespirable spray 61 that passes through the patient port 57 into thepatient's body cavity (e.g., oral cavity and/or nasal cavity) and thenceinto their respiratory passages, thereby treating their disease.

Important aspects of such a conventional pMDI device 50 that have thepotential to limit its efficacy are, in particular, its fixed lowresistance to air flow and its need for good patient coordinationbetween the timing of the start of inhalation and the moment at whichthe canister 51 is pressed downwards. The latter is a challenge for ahigh proportion of patients, leading to poor and often highly varyingefficacy of medicament administration.

The low resistance air flow path is best described with reference toFIG. 1. As the patient inhales on the patient port 57, i.e. as theyreduce the air pressure in their own respiratory passages and oralcavity and in the patient port 57 via outward movement of their chestwall and downwards movement of their diaphragm, an air flow is set upthrough the pMDI device 50. Air from the atmosphere external to theinhaler, i.e., ambience, is drawn into the inhaler via an air flow path46 of the pMDI device 50, e.g., beginning with the annular gap betweenthe can 53 and the open tubular sleeve portion 56 of the housing 55,passing down the sleeve portion 56 along the length of the can 53, andturning the corner into the wide passageway inside the mouthpiece 57.The mouthpiece passageway clearly needs to be open and wide to allow themedicament spray 61 to emerge. The annular gap also has a largecross-sectional area that is approximately a product of the canisterdiameter (typically 22-23 mm) and the clearance required between thecanister 51 and the housing sleeve portion 56 to ensure that thecanister 51 does not scrape or jam within the housing 55. Typically thisclearance is 2 mm or more, giving an approximate air flow pathcross-sectional area of in excess of 40 mm². At the typical patientinspiratory pressure drops of 0.5 to 8 kPa, that cross-section presentsvery little effective resistance to inspiratory air flow. It is thuseasy for many patients to draw an excessive and uncontrolled flow rateof air through the inhaler, leading to poorly controlled andinconsistent medicament delivery to their lungs.

FIG. 2 shows, schematically, some fairly typical chronic obstructivepulmonary disease (COPD) patient inspiratory flow rate (L/min.) versustime (seconds) profiles. In the absence of significant inhalation deviceresistance to air flow, some profiles 29 are characterised by a short,relatively rapid intake of breath. Other patients, e.g. with weakerlungs, are unable to either sustain long inhalations or to achieveadequate flow rates. Their profiles 31 are short and weak. Using aninhaler that comprises a flow governor of the present disclosure,however, can provide patient inspiratory profiles that are more likethat denoted as 33: a longer, sustained, steady inspiratory flow rate(e.g., of around 30 L/min.) can be obtained.

COPD patients have a wide range of inhalation breathing capability andthis can be represented as a distribution between 0.5 and 4 kPa pressuredrop. In some embodiments, the static resistance of an inhaler of thepresent disclosure prior to any governing of flow by the flow governorof the present disclosure (i.e., prior to any collapse of the tubularelement) can be approximately 0.8 Pa^(0.5) min./L. This can beconsidered to be a medium resistance. In some embodiments of the presentdisclosure, the target governing flow rate can be 30 L/min. In someembodiments, the target breath-actuation triggering flow rate can be 15L/min. With such a system, there is very low probability of a COPDpatient not being able to reach the triggering flow rate, either throughlack of inhalation effort or because any individual flow governor limitsthe air flow rate to less than its breath-actuation triggering flowrate. Such an inhalation device is therefore suitable for a very highproportion of COPD patients. That is, at low flow rates, the inhalerwill operate like a medium resistance device, and every patient will beable to inhale up to 20 L/min. quite easily. At a somewhat greater flowrate, the flow governor's tubular element will collapse onto theinternal support structure, and the inhaler will become a highresistance device. The patient will then not be able to inhale at ahigher flow rate. In general, patients are likely to learn toautomatically compensate their inhalation effort and will continue toinhale at a flow rate that is comfortable to them. For some patients,that will involve a pressure drop of only 0.5 kPa, but for others itwill be 4 kPa or above depending upon their lung strength and capacityand upon the training the patient has previously had.

If a higher flow governor flow rate were selected (e.g., greater than 30L/min.), then some patients would not be able to achieve the air flowrate required for the inhaler to be governed, and the variability inpatient inhalation would not be minimized. If, alternatively, theinhaler were to have a higher resistance, then again some patients wouldnot be able to achieve the governed flowrate and the variability inpatient inhalation flowrate would not be minimized. With the parametersdescribed above, however, an inhaler incorporating a flow governor ofthe present disclosure has the potential to:

-   -   Improve coordination of drug release with the start of        inspiratory flow;    -   Maintain the inspiratory air flow rate to within a range of        approximately 25 to 35 L/min.; and    -   Reduce variability both in dose consistency and the location of        drug deposition in the lung.

For a nominal target governing flow rate of 30 L/min., there will be arange of actual values due to manufacturing tolerances and environmentalfactors such as temperature and atmospheric pressure. In an embodimentwhere the inhaler's total static resistance is 0.83 Pa^(0.5)(minl⁻¹),and the flow governor has a nominal governing flow of 30 L/min., anypatient inhaling at a pressure drop between 0.5 kPa and 4 kPa would beexpected to generate an air flow of between about 25 and 35 L/min.

In some embodiments of the present disclosure, the governing flow ratecan be nominally 40 L/min. In this case, patients who can only produce alow inhalation pressure drop (e.g. about 0.5 kPa) and who typicallyinhale at less than 40 L/min. will not benefit from the flow governor,and their inhalation will be equivalent to inhaling through a mediumresistance inhaler. Other patients who naturally inhale more strongly(i.e. at a higher pressure drop) are likely to benefit from the flowgovernor, and their flow rate will be restricted by the flow governor tothe governing flow rate.

In some embodiments of the present disclosure, the governing flow ratecan be nominally 50 L/min. In this case, only patients who inhale at apressure drop of greater than approximately 1.5 kPa will experience flowgoverning. Because the governing flow rate is higher, there will be alarger spread in the Peak Inhalation Flow rates (PIF) obtained betweenpatients: some will be able to inhale at only around 27 L/min. becausethis is the fastest that they can inhale through a medium resistancedevice, whereas others who inhale at 4 kPa could pull as much as 55L/min. through the system.

Additional illustrations of the effects of flow governors are detailedbelow in the Examples section.

FIGS. 3-14 illustrate various embodiments of flow governors of thepresent disclosure. FIGS. 15-19 illustrate various embodiments ofmedicinal inhalers of the present disclosure that comprise a flowgovernor of the present disclosure. FIGS. 20-23 illustrate variousembodiments of flow governor assemblies of the present disclosure,comprising flow governors that can be employed in medicinal inhalers.

Flow Governors

FIGS. 3-8 illustrate a flow governor 101 according to one embodiment ofthe present disclosure. FIGS. 3-6 show the flow governor 101 at rest,and FIGS. 7-8 show the flow governor 101 in operation.

As shown, the flow governor 101 includes an outer flexible tubularelement (or “tube”) 102 comprising at least one flexible wall 140, andan internal support structure 103 that is dimensioned to be receivedwithin the tubular element 102 (i.e., within the at least one flexiblewall 140). In the embodiment of FIGS. 3-8, the internal supportstructure 103 includes a hollow base 104, two hollow (e.g., tubular)pillars 105 and a cross member (or “crossbeam”) 106.

The outer diameter of the hollow base 104 of the illustrated embodimentis greater than an initial inner diameter of the tubular element 102,and assembly of the two components can be achieved by stretching thetubular element 102 over an outer portion (e.g., an outer wall) of thehollow base 104. This positioning results in the originally circularcross-section of the tubular element 102 being deformed into anapproximately elliptical (or oblong) cross-sectional (i.e., intransverse cross-section) shape. In some embodiments, such anelliptically-shaped tubular element 102 can have a major axis(externally) of approximately 12 mm and a minor axis (externally) ofapproximately 4 mm.

Other formation and/or assembly means are alternatively possible,however, as will be apparent to a person of ordinary skill in the art.For example, the tubular element 102 could instead be over-molded ontoan outer surface of the hollow base 104 of the internal supportstructure 103, or it could be stretched and then coupled to the outersurface of the base 104 by a variety of coupling means, including, butnot limited to, one or more of adhesives, cohesives, welding (e.g.,sonic [e.g., ultrasonic] welding), any thermal bonding or heat sealingtechnique (e.g., heat and/or pressure applied to one or both of thecomponents to be coupled), other suitable coupling means, orcombinations thereof.

In some embodiments, the internal support structure 103 can be coupledto or integrally formed with a portion of a housing that forms an airflow path or an inhaler of the present disclosure. For example, in someembodiments, the internal support structure 103 can be provided by(e.g., integrally formed with) the housing that forms at least a portionof an inhaler housing.

As shown in FIGS. 3-6, the flow governor 101, and the tubular element102, can be substantially linear. Furthermore, the flow governor 101 canhave an air flow path 107 including an air inlet 108 located at a first(longitudinal) end and an air outlet 109 located at a second(longitudinal) end that generally define an air flow direction that isgenerally oriented along a longitudinal direction D. The tubular element102 can be elongated in the longitudinal direction D. The at least oneflexible wall 140 of the tubular element 102 can be orientedsubstantially parallel to the longitudinal direction D; the hollowpillars 105 can be oriented substantially parallel to the longitudinaldirection D; and the cross member 106 can be oriented at a non-zeroangle (e.g., substantially perpendicularly) with respect to thelongitudinal direction D, i.e., substantially parallel with respect to alateral direction L (which can represent a side-to-side direction of theflow governor 101). A third transverse direction T is orientedsubstantially perpendicularly with respect to the longitudinal directionD and the lateral direction L, and can represent a front-to-backdirection of the flow governor 101.

The tubular element 102 (i.e., the at least one flexible wall 140) canbe formed of a variety of materials, including, but not limited to, oneor more of silicone rubber, other thermoplastic elastomers, orcombinations thereof. In addition to its flexibility, the tubularelement 102 can be formed of a material that is resilient, in order thatit returns to its rest shape and position when air flow through itceases, i.e., the tubular element 102 can deform elastically and springback ready for its next cycle of use. The material may be chosenaccording to specific property needs, e.g. if it is to be over-molded,glued or ultrasonically welded to the hollow base 104 of the internalsupport structure 103. It will be obvious to one skilled in the art thatthe chosen tubular element material should have good long term physicaland chemical stability.

While the tubular element 102 can suitably have a relaxed transversecross-sectional shape that is substantially circular (and which can bestretched to an elliptical cross-sectional shape over the base 104 ofthe internal support structure 103), other cross-sectional shapes arepossible, such as those described above in the definition of “tubular.”It should also be noted that the base 104 can be elliptical in itstransverse cross-sectional shape or can be another shape. In someembodiments, the base 104 is elliptical, the ellipse having the specialcase shape of a circle. In some embodiments employing a transversecross-sectional shape of the base 104 that is circular, or is close tocircular, can assist in ensuring that the tubular element 102 can beassembled onto it without imposing significant residual torsionalstrains into it. Furthermore, in some embodiments, the tubular element102 can be formed of more than one material, or can have differentsections (e.g., sequentially along its longitudinal direction) withdifferent wall thicknesses and/or diameters, such that certain sectionsof the tubular element 102 are more flexible than others and canpreferentially collapse.

In some embodiments, the tubular element 102 can be formed of a siliconerubber tube of approximately 0.3 mm wall thickness, 8.0 mm initialinside diameter, 20 mm length and 60 OO Shore hardness.

In some embodiments, the internal support structure 103 can have an “H”shaped longitudinal cross-sectional shape (i.e., taken along thelongitudinal direction D), as shown in FIG. 4. However, as shown in FIG.4, in some embodiments, the cross member 106 may not be longitudinallycentered with respect to the overall dimension (e.g., height) of theinternal support structure 103 in the longitudinal direction D, butrather, the cross member 106 may be located toward the air inlet end(e.g., an upstream end) of the internal support structure 103.

Additionally, or alternatively, in some embodiments, the internalsupport structure 103 can have a generally “H” shaped (i.e., generallysimilar to a capital English letter H) transverse cross-sectional shape(i.e., taken substantially orthogonally with respect to the longitudinaldirection D, e.g., in the lateral direction L or the transversedirection T), as shown in FIG. 5. Furthermore, in some embodiments, theinternal support structure 103 can be formed of an injection moldedplastic, such as polypropylene, acetal, ABS (acrylonitrile butadienestyrene), polycarbonate or polyethylene, or can be made from a metal ormetal alloy (e.g., machined, stamped/pressed or metal injection molded)or from a ceramic material (e.g. ceramic injection molded). In someembodiments, the internal support structure 103 can be formed as asingle integral component, i.e., formed from one part.

As shown in FIG. 5, in some embodiments, the cross member 106 of theinternal support structure 103 can be substantially centered withrespect to the pillars 105 in the transverse direction T, which givesthe generally “H” shaped transverse cross-sectional shape. In addition,by way of example, the illustrated internal support structure 103 ofFIGS. 3-8 has lateral symmetry about a central longitudinal axis (i.e.,about a central transverse-longitudinal plane), as well as transversesymmetry (e.g., front-to-back) about the central longitudinal axis(i.e., about a central lateral-longitudinal plane). Said another way,the internal support structure 103 is symmetrical about a centrallongitudinal axis in the lateral direction D and the transversedirection T.

As will be described in greater detail below, only the air outlet end ofthe tubular element 102 is fixed and supported (i.e., by the base 104 ofthe internal support structure 103), whereas the air inlet end of thetubular element 102 is freestanding and able to collapse onto theinternal support structure 103.

The assembly of the tubular element 102 and the internal supportstructure 103 forms the air flow path 107, including the air inlet 108and the air outlet 109. FIG. 5 shows a transverse cross-section of theflow governor 101, which illustrates that the tubular element 102 has anapproximately elliptical cross-section once stretched onto the base 104of the internal support structure 103, and also shows two lumens 110,located within the two hollow pillars 105, which act as residual airflow channels, i.e., function as a portion of the air flow path 107through the flow governor 101. By way of example only, the lumens 110are shown as having an approximately triangular shape in the transversecross-section. In some embodiments, each of the two lumens 110 can havean open cross-sectional area of approximately 1 mm².

FIG. 6 shows a side longitudinal cross-section of the flow governor 101,which illustrates that the tubular element 102 runs substantiallyparallel to the hollow pillars 105, but is not in contact with them. Atthe air inlet 108, the hollow pillars 105 can protrude from the tubularelement 102. With reference to FIG. 4, it may be noted that air flowentering the pillar lumens 110 will exit at a bypass outlet 111 of eachpillar 105, prior to passing through the hollow base 104.

One primary function of the flow governors of the present disclosure isto govern air flow when the patient inhales through a medicinal inhaler,limiting the patient's inspiratory flow rate to a narrow and controlledrange in order to avoid excessively fast inhalation and consequentlyexcessive mouth and throat drug deposition. The flow governors ofpresent disclosure are thus able to aid in the attainment of increaseddeep lung drug penetration and deposition.

Use of such a flow governor allows patients with poor lung function(e.g. particularly poorly COPD patients) to experience a relatively lowinhaler air flow resistance (allowing them to inhale sufficient air in areasonable degree of comfort) while giving patients with stronger lungsa transiently higher air flow resistance to inhale against (therebyallowing them to inhale for longer and more deeply, while at the sametime limiting their inhalation air flow rate to a level very similar tothat of weaker patients). In other words, the inspiratory air flow ratecan be kept much more consistent between patients and betweeninhalations. Medication delivery is thus much more predictable, allowingphysicians to prescribe treatment regimes with an improved level ofconfidence.

While FIGS. 3-6 illustrate the flow governor 101 at rest (i.e., with thetubular element 102 in an uncollapsed state); FIGS. 7 and 8 show theflow governor 101 in an operative state (i.e. with the patient'sinspiratory air flow substantially passing through it and with thetubular element 102 in a collapsed state). When air is sucked towardsthe air outlet 109, it flows via the air inlet 108 into the air flowpath 107, around the pillars 105 and cross member 106 (i.e., through anygap still present between the pillars 105 and the tubular element 102and between the cross member 106 and the tubular element 102), andthrough the pillar lumens 110. The speed of the passing air flow throughthe air flow path 107 creates a reduction in air pressure in the airflow path 107 (i.e., according to the Bernoulli Effect). In theembodiment illustrated in FIGS. 3-8, the reduced pressure in the airflow path 107 causes a reduction in the diameter along the minor axis ofthe elliptical cross-sectioned tubular element 102 (i.e., in thetransverse direction T) resulting in inward bending, as shown in FIGS. 7and 8. Because the tubular element 102 is supported at one end (i.e.,its outlet end, toward the air outlet 109) by the hollow base 104, theinward bending occurs predominantly at the end of the tubular element102 that is towards the air inlet 108, the inward bending restrictingthe cross-sectional area of the air flow path 107.

To an extent, the greater the reduction in pressure in the air flow path107, the greater the inward bending of the tubular element 102. Theresultant reduction in the cross-sectional area of the air flow path 107leads to an increased resistance to air flow rate. However, because theair flow path 107 of the flow governor 101 is only one part of the totaloverall resistance to air flow of the medicinal inhaler in which theflow governor 101 is employed (e.g. it might be around 50% or less ofthe total inhaler air flow resistance if the inhaler has a moderatestatic resistance to air flow), then the mass flow rate of air throughthe flow governor 101 does not fall in proportion to its reducedresidual cross-sectional area. This means that the velocity of airthrough the residual air flow path 107 within the collapsed tubularelement 102 rises as the tubular element 102 collapses, furtherincreasing the Bernoulli forces upon it. This effect tends to lead tosubstantial bistability in the operation of the flow governor 101. Thatis, the initiation of collapse leads to “positive feedback” whichreinforces the inwards collapse-driving Bernoulli forces until they areeventually balanced by the resistive stiffness forces of the material ofthe tubular element 102. In other words, in some embodiments, the flowgovernor 101 can be substantially bistable, where it tends to be in oneof two states at any time: either it is in a substantially ‘open’ or‘uncollapsed’ state, or it is in a substantially ‘collapsed’ state.

Complete collapse of the elliptical cross-section tubular element 102 isprevented by the hollow pillars 105. These pillars 105, together withthe cross member 106, provide structural support that preventssignificant reduction in the diameter along the major axis of theelliptical cross-section tubular element 102 (i.e., in the lateraldirection L). The air flow bypasses provided by the lumens 110 allow abase level of residual air flow to continue to flow. In addition, thefinite stiffness of the tubular element 102 means that small additionalgaps are left around the corners of the internal support structure 103where the tubular element 102 cannot bend sufficiently to close off allthe small residual air passageways or gaps between the internal supportstructure 103 and the tubular element 102 (see, e.g., FIG. 7). Thus, atleast a minimum, or residual, air flow can always continue to flow. Thatis, the reduced pressure can never reach a value sufficient for thetubular element 102 to collapse completely and to seal off all air flowthrough the flow governor 101.

The point at which the tubular element 102 collapses and the flow rateat which the flow governor governs are dependent on the geometry of theinternal support structure 103 (and particularly, on the cross-sectionalarea of the pillar lumens 110), and the properties of the tubularelement 102, in particular its wall thickness, air inlet cross sectionalarea, width, length and Shore hardness. For the tubular element 102,material that has a low adhesive characteristic can also be preferable,to ensure a smooth transition from the collapsed to the open state byprevention of adhesion to a housing wall of an inhaler in which the flowgovernor 101 is positioned and/or to the internal support structure 103.

As described in greater detail in the Examples section, mathematicalmodeling of flow governors of the type shown in FIGS. 3-8 hasdemonstrated that the flow governors of one embodiment of the presentinvention are capable of governing at an air flow of 30 L/min. with arepeatability and consistency of ±5 L/min. over a wide range of patientpressure drops. Almost all patients, even those with very weak lungs,should be capable of achieving such air flow rates, yet because of theoperation of the flow governor, no patients are likely to be able toexceed such air flow rates, even with very excessive effort.

Other arrangements of the embodiment described, such as the shape, size,number and location of elements belonging to the internal supportstructure, will be apparent to one skilled in the art.

Other designs or configurations of the internal support structure may beused instead of the hollow pillar and cross member arrangement of FIGS.3-8. For example, FIGS. 9-14 illustrate various flow governors of thepresent disclosure, wherein like numerals represent like elements. FIGS.9-13 illustrate a flow governor 201 according to another embodiment ofthe present disclosure that employs a different internal supportstructure; and FIG. 14 illustrates a flow governor 301 according to yetanother embodiment of the present disclosure. The flow governors ofFIGS. 9-14 share many of the same elements, features, and functions asthe flow governor 101 of FIGS. 3-8. Reference is made to the descriptionabove accompanying FIGS. 3-8 for a more complete description of thefeatures and elements (and alternatives to such features and elements)of the embodiments illustrated in FIGS. 9-14. Any of the featuresdescribed above with respect to FIGS. 3-8 can be applied to theembodiments of FIGS. 9-14, and vice versa.

With reference to FIGS. 9-13, the flow governor 201 includes a tubularelement 202 comprising at least one flexible wall 240, and an internalsupport structure 203. In this embodiment, the internal supportstructure 203 includes a hollow base 204, solid pillars 205 (i.e., withno lumens), a cross member 206, and one or more splines (or transverseprotrusions or transverse splines) 213 (see FIGS. 10 and 12) protrudingfrom the cross member 206 (e.g., protruding transversely from thelaterally oriented cross member 206). In some embodiments, as shown, theone or more transverse protrusions 213 can be located laterallycentrally with respect to the internal support structure 203 andprotruding forwardly and rearwardly with respect to the cross member 206(i.e., when viewed in transverse cross-section, as shown in FIG. 10). Insome embodiments, the one or more transverse protrusions 213 canprotrude from the internal support structure 203 substantiallyorthogonally with respect to the at least one flexible wall 240 of thetubular element 202.

By way of example only, the internal support structure 203 has an “H”shaped longitudinal cross-sectional shape (i.e., taken along thelongitudinal direction D), as shown in FIG. 9 and a generally “H” shapedtransverse cross-sectional shape (i.e., taken substantially orthogonallywith respect to the longitudinal direction D, e.g., in alateral-transverse plane), as shown in FIGS. 10 and 12.

Furthermore, in embodiments employing at least one transverse protrusion213, the internal support structure 203 can further include a transversecross-sectional shape including at least one capital English letter “E.”Particularly, in embodiments employing two laterally-centered transverseprotrusions 213, as shown in FIGS. 10 and 12, the internal supportstructure 203 can have a transverse cross-sectional shape including twocapital letter “E”s, merged back-to-back and oriented with the long sideof the “E” in the lateral direction L. Unlike the hollow pillars 105 ofFIGS. 3-8, the solid pillars 205 lack any internal lumen with longaspect ratios, and therefore have a geometry that may be more desirablefor ease of manufacture. Other arrangements, not necessarily “H”-shapedin longitudinal or transverse cross-section, will also be apparent toone skilled in the art. Examples include flow governors having one ormore internal support structures having transverse cross-sectionalshapes including, or similar to, any of the letters selected from theEnglish capital letters of B, C, D, E, H, M, N, O, S, V, W, X and Z.Other shapes will also be apparent to one of ordinary skill in the art.

FIGS. 9-11 illustrate the flow governor 201 at rest (i.e., with thetubular element 202 in an uncollapsed state), and FIGS. 12-13 illustratethe flow governor 201 in an operative state (i.e., with the tubularelement 202 in a collapsed state).

The flow governor 201 includes an air flow path 207 formed between theinternal support structure 203 and the tubular element 202, the air flowpath 207 including an air inlet 208 and air outlet 209. FIG. 10 shows atransverse cross-section of the flow governor 201, taken generallyperpendicularly with respect to the general direction of air flow, whichillustrates that the tubular element 202 has an approximately ellipticaltransverse cross-sectional shape at rest. In some embodiments, as shown,the splines 213 protrude outwardly from the cross member 206 (e.g., inthe transverse direction T) less than the solid pillars 205 do. Inalternative embodiments, the splines can be dimensioned to protrude anequal distance from the cross member 206 as the solid pillars 205, oralternatively, can protrude further. Alternatively, each solid pillar205 can have a transverse cross-sectional shape in the form of a crossrather than an approximate rectangle. Many more variants to thecross-sectional shape and dimensions of the internal support structure203 are possible, as will be apparent from these examples. Each variantwill have its own air flow characteristics as a function of pressuredrop and air flow rate, in combination with the characteristics of theform and material of the tubular element 202.

FIG. 11 illustrates that the tubular element 202 and the solid pillars205 are oriented generally parallel to the longitudinal direction D, andthat the tubular element 202 is not in contact with the solid pillars205 at rest, and that the pillars protrude from the tubular element 202at the air inlet 208 (i.e. protrude from an upstream end of the tubularelement 202.

FIGS. 12 and 13 illustrate the flow governor 201 in an operative state.When air is sucked through the air outlet 209, it flows into the airflow path 207 via the air inlet 208. As shown, the reduced air pressurecreated by the patient's inhalation causes a reduction in diameter alongthe minor axis of the elliptically sectioned tubular element 202resulting in inward bending as shown in FIG. 12. As the tubular element202 is supported at the downstream end by the hollow base 204, inwardbending occurs predominantly at the end of the tubular element 202 thatis nearer to the air inlet 208, the inward bending restricting thecross-sectional area of the air flow path 207. The lower the airpressure in the air flow channel 207, the greater the inward deformationof the tubular element 202 and hence, the greater the reduction in thecross-sectional area of the air flow path 207 and the greater theresistance to air flow.

Complete collapse of the elliptical cross-sectioned tubular element 202is prevented by the solid pillars 205. These structures, along with thecross member 206, provide structural support that prevents significantreduction in the diameter along the major axis of the ellipticallysectioned tubular element 202. The splines 213 additionally providesupport along the minor axis, preventing the tubular element 202 (andparticularly, the at least one flexible wall 240) from collapsing tootightly onto the cross member 206. Residual air flow is thus alwayspossible via the residual air flow channel gaps, no matter how great thepatient's inspiratory pressure drop.

FIG. 14 illustrates a flow governor 301 according to another embodimentof the present disclosure. The flow governor 301 includes a tubularelement (or “tube”) 302 comprising at least one flexible wall 340, andan internal support structure 303 that is dimensioned to be receivedwithin the tubular element 302 (i.e., within the at least one flexiblewall 340). The tubular element 302 surrounds and envelopes the internalsupport structure 303. The internal support structure 303 consists of ahollow base 304, two hollow pillars 305 (each comprising a lumen 310),and a cross member 306. As shown in FIG. 14, in some embodiments, thetubular element 302 can be anchored or otherwise attached (e.g., to theinternal support structure 303) at both ends, rather than being free atthe air inlet end. As shown in FIG. 14, in some embodiments, the crossmember 306 can be located longitudinally centrally with respect to thepillars 305. As a result, in addition to the lateral and transversesymmetries of previous embodiments, the internal support structure 303(and the flow governor 301) can also have longitudinal symmetry (e.g.,about a central lateral-transverse plane).

As with previous embodiments, the outer diameter of the hollow base 304is larger than the inner diameter of the flexible tubular element 302,and assembly of the two components is achieved by stretching the tubularelement 302 over the outer surface of the hollow base 304. The tubularelement 302 and the internal support structure 303 together define anair flow path 307 therebetween that includes an air inlet 308 and an airoutlet 309. The air flow path 307 also includes the lumens 310 throughthe pillars 305. When air is sucked towards the air outlet 309, it flowsinto the air flow path 307 and through (i.e., via) the lumens 310 andaround the pillars 305 via the air inlet 308, creating a reduction inair pressure in the air flow path 307 by the Bernoulli Effect. Thereduced pressure in the air flow path 307 causes a reduction in thediameter along the minor axis of the elliptical cross-section of thetubular element 302 centered at approximately the midpoint of the airflow path 307.

One possible advantage of having the tubular element 302 secured at bothends is that the tubular element 302 can be of greater thickness for agiven flow governing performance, thereby offering a manufacturingadvantage with regard to the dimensional specification range of thetubular element 302. Another possible advantage of having the tubularelement 302 secured at both ends is that the use of a symmetricalarrangement (e.g., symmetrical longitudinally, laterally andtransversely) can offer a manufacturing benefit, as it does not requirea consistent and specified end-to-end orientation during assembly.

FIGS. 26 and 27 illustrate a flow governor 1001 according to anotherembodiment of the present disclosure that employs a different internalsupport structure. The flow governor of FIGS. 26 and 27 shares many ofthe same elements, features, and functions as the flow governors ofFIGS. 3-14. Reference is made to the description above accompanyingFIGS. 3-14 for a more complete description of the features and elements(and alternatives to such features and elements) of the embodimentillustrated in FIGS. 26 and 27. Any of the features described above withrespect to FIGS. 3-14 can be applied to the embodiment of FIGS. 26 and27, and vice versa.

With reference to FIG. 26, a side cross-sectional view of the flowgovernor 1001 including a tubular element 1002 comprising at least oneflexible wall 1040 and an internal support structure 1003 is shown. Inthis embodiment, the internal support structure 1003 includes a hollowbase 1004, solid pillars 1005 (i.e., with no lumens), and a cross member1006. In this embodiment, the tubular element 1002 runs substantiallyparallel to the solid pillars 1005, but is not in contact with them.

At the air inlet 1008, the solid pillars 1005 protrude from the tubularelement 1002. In addition, the cross member 1006 is located outside thetubular element 1002 at the air inlet 1008. In FIG. 26, the cross member1006 is positioned at the ends of the solid pillars 1005. In someembodiments, the cross member may be positioned some distance from theends of the pillars, provided the cross member is located outside thetubular element.

By way of example only, the internal support structure 1003 has aninverted “U” shaped longitudinal cross-sectional shape when viewed infront longitudinal cross-section view, as shown in FIG. 26 and agenerally “H” shaped transverse cross-sectional shape (i.e., when viewedsubstantially orthogonally with respect to the longitudinal direction D,e.g., in a lateral-transverse plane), as shown in FIG. 27.

Any of the various alternatives for the designs of the pillars and crossmembers described herein may be used. Two such exemplary embodiments areillustrated in FIG. 28. As shown in FIG. 28A, an internal support 1023includes a cross member 1026 connected to two pillars 1025, which arehollow such that they include lumens 1020. Alternatively, as shown inFIG. 28B, a cross member 1016 may be generally “O” shaped (e.g.,circular or elliptical). Such a cross member may be mounted between oron top of pillars (not shown) to form the support structure. If thecross member is located inside the tubular element, the cross memberwill contribute to the overall flow restriction and the resulting flowrates and pressure drops. By locating the cross member outside thetubular element beyond its upstream end, the cross member can stillcontribute to the structural integrity of the support structure withoutblocking any portion of the interior of the tubular element. As aresult, by locating the cross member outside the tubular element, lowerinitial resistances and higher average flow rates may be achievedcompared to similar support structures where the cross member is locatedwithin the tubular element.

Medicinal Inhalers

FIG. 15 illustrates a medicinal inhaler 250 according to one embodimentof the present disclosure that employs a flow governor 101 of thepresent disclosure. By way of example only, the medicinal inhaler 250 isshown in FIG. 15 as including the flow governor 101 of FIGS. 3-8;however, it should be understood that any flow governor of the presentdisclosure can be employed in the inhaler 250. By way of furtherexample, the medicinal inhaler 250 is shown as being a press-and-breathepressurized metered dose inhaler (pMDI).

The inhaler 250 shares many of the elements, features, and functions ofthe pMDI 50 of FIG. 1, wherein like numerals represent like elements. Asa result, reference is made to the description above accompanying FIG. 1for a more complete description of the features and elements (andalternatives to such features and elements) of the inhaler 250 of FIG.15.

The inhaler 250 includes a canister 251 containing a medicamentformulation 252, the canister comprising a can 253 sealed with ametering valve 254. The canister 251 sits within a housing (or“actuator”) 255 comprising an initially open tubular sleeve portion 256having a first open end 247 dimensioned to receive the canister 251 andfrom which its base 249 can protrude, and a portion in the form of anopen tubular mouthpiece 257. The open housing 255 can define an air flowpath 246 therein, in particular from an air inlet 215, open to ambience,to the mouthpiece 257 that defines an inhalation orifice or an airoutlet 245. A stem portion 258 protrudes from the metering valve 254 andis located and retained by friction in a stem socket 259 formed as anintegral part of the housing 255. A spray orifice 260 is formed in thestem socket 259, and provides a passage for fluid communication betweenthe valve stem portion 258 and the mouthpiece 257.

As further shown in FIG. 15, the inhaler 250 further includes the flowgovernor 101 incorporated directly into the inhaler 250 by beingpositioned in the air flow path 246 of the inhaler 250. Particularly, inthe embodiment of FIG. 15, the flow governor 101 is located in adedicated tubular air flow path 214 between the air inlet 215 and an airoutlet 216 in fluid communication with the air outlet 245 of the inhaler250, such that the air flow path 214 forms a portion of the overall airflow path 246 of the inhaler 250.

By way of example only, the dedicated air flow path 214 is located at arear portion of the housing 255 (i.e., opposite the mouthpiece 257) andis integrally formed with the housing 255. By way of further example,the air inlet 215 is defined by a second open end 220 of the housing255, wherein the second open end 220 is dimensioned to receive the flowgovernor 101. As a patient inhales on the mouthpiece 257, air flows viathe air inlet 215 into the flow governor 101, creating the reducedpressure required to activate the flow governor 101, thus regulating theair flow. In order to avoid any ingress of air from the top of theinhaler 250 that would bypass the flow governor 101, a cover 217 thatforms a seal is located over the first open end 247 of the housing 255.The cover 217 can be flexible, in order to allow the base 249 of thecanister 251 to still be depressed to deliver the dose of medicamentformulation. This flexibility can be provided via appropriate choice ofmaterial(s) of manufacture for the cover 217, via the cover geometry anddesign, or both.

The dedicated air flow path 214 is shown as being substantially constantin cross section in FIG. 15; however, this need not be the case. Variouspossible shapes and configurations for air flow paths including a flowgovernor of the present disclosure and for being incorporated into amedicinal inhaler of the present disclosure are described in greaterdetail below with reference to FIGS. 20-23.

FIG. 16 illustrates a medicinal inhaler 350 according to anotherembodiment of the present disclosure. The inhaler 350 shares many of theelements, features, and functions of the inhalers 50 and 250 of FIGS. 1and 15, respectively, wherein like numerals represent like elements. Asa result, reference is made to the description above accompanying FIGS.1 and 15 for a more complete description of the features and elements(and alternatives to such features and elements) of the inhaler 350 ofFIG. 16.

The inhaler 350 includes a housing 355 that defines an air flow path 346therethrough, including an open end 320 and an air outlet 345 (formed bya mouthpiece 357). The housing 355 also includes an initially opentubular sleeve portion 356 having an open end 347 dimensioned to receivea canister 351 comprising a medicament formulation 352. The inhaler 350further includes the flow governor 101 (i.e., by way of example only)positioned in the air flow path 346 extending from the open end 320 tothe air outlet 345. Particularly, similar to the embodiment of FIG. 15,the flow governor 101 is positioned in a dedicated air flow path 314that is open to ambience (e.g., via the open end 320) and in fluidcommunication with, and forms a portion of, the overall air flow path346 of the inhaler 350. In addition, the dedicated air flow path 314 isintegrally formed with the housing 355, and particularly is formed in arear portion of the housing 355, i.e., opposite the mouthpiece 357.

FIG. 16 illustrates an alternative system for sealing the open end 347of the housing 355 of the inhaler 350 to avoid bypass air ‘defeating’the flow governor 101. In this embodiment, a skirt seal 318 is used toseal or substantially seal the gap around the canister 351. That is, theskirt seal 318 is located between an outer surface 322 of the canister351 (and particularly, an outer surface 322 of a can 353 of the canister351) and an inner surface 324 of the housing 355 (and particularly, aninner surface 324 of the sleeve portion 356 of the housing 355) to sealthe open end 347 (i.e., the sleeve portion 356 of the housing 355) fromambience.

The skirt seal 318 can be formed of a thin and flexible annularelastomer and can be made sufficiently flexible to avoid introducing anygreat resistance to longitudinal canister movement in the sleeve portion356 of the housing 355. Other arrangements of sealing components will beapparent to one skilled in the art.

FIG. 17 illustrates a medicinal inhaler 450 according to anotherembodiment of the present disclosure. The inhaler 450 shares many of theelements, features, and functions of the inhalers 50 and 250 of FIGS. 1and 15, respectively, wherein like numerals represent like elements. Asa result, reference is made to the description above accompanying FIGS.1 and 15 for a more complete description of the features and elements(and alternatives to such features and elements) of the inhaler 450 ofFIG. 17.

The inhaler 450 includes a housing 455 that defines an air flow path 446therethrough, including an air passage 469 and an air outlet 445.Particularly, the housing 455 includes an open tubular sleeve portion456 having an initially open end 447 that defines the air passage 469,and a mouthpiece 457 that defines the air outlet 445. The sleeve portion456 and the open end 447 are dimensioned to receive a canister 451comprising a medicament formulation 452. The inhaler 450 furtherincludes the flow governor 101 (i.e., by way of example only) positionedin the air flow path 446.

FIG. 17 illustrates another alternative system for sealing the open end447 of the housing 455 of the inhaler 450 to avoid bypass air‘defeating’ the flow governor 101. In this embodiment, rather thanhaving the flow governor 101, or a dedicated air flow path, form aportion of or be built into the housing 455 of the inhaler 450, the flowgovernor 101 is located in a cap 426 configured to be coupled to (e.g.,clipped or snapped onto) the initially open end 447 of the housing 455to close and seal the open end 447, such that the cap 426 ends upforming a portion of the air flow path 446 when coupled to the housing455. As a result, the cap 426, when coupled to the housing 455, definesthe air inlet of the air flow path 446 of the inhaler 450, such thatinhaled air must pass through the flow governor 101 in the cap 426. Inthis embodiment, the cap 426 can be provided as a retro-fitted accessoryto an existing inhaler.

Similar to the cover 217 of FIG. 15, the cap 426 can be formed of aflexible material to allow the canister 451 to still be pressed whendesired. In addition, or alternatively, as shown in FIG. 17, in someembodiments, the inhaler 450 can include a button 419 to allow thecanister 451 to be pressed to release a dose of medicament. For example,in some embodiments, the button 419 can be fixed with respect to the cap426, and the cap 426 can be flexible. In some embodiments, the cap 426need not be flexible, and the button 419 can be movable with respect tothe cap 426.

In other embodiments, the flow governors of the present disclosure canbe built into other locations within an inhaler. For example, the flowgovernor could be positioned below the foot of the stem socket (see,e.g., the stem socket 59 of FIG. 1) into which the valve stem portion(see, e.g., the stem portion 58 of FIG. 1) of the canister (see, e.g.,the canister 51 of FIG. 1) locates. In such embodiments, e.g., its inletcan be positioned below the mouthpiece of the inhaler (see, e.g., themouthpiece 57 of FIG. 1), and its outlet could be arranged to feed airto the stem socket region. A sealing cover (see, e.g., the cover 217 ofFIG. 15), a skirt seal (see, e.g., the skirt seal 318 of FIG. 16), oranother sealing means can be employed over the open end of the housingthat receives the canister of medicament to avoid any air bypassing theflow governor.

In any of the inhalers of the present disclosure employing flowgovernors of the present disclosure, grill structures can be providedover the air inlet of the air flow path in which the flow governor islocated, such that large pieces of debris, for example, are notinadvertently taken into the inhaler device. Furthermore, in eachembodiment of the inhaler of the present disclosure, the air inlet ofthe flow governor air flow path is preferably positioned where it willnot readily be inadvertently blocked or obstructed by a patient's lips,fingers, etc., during use.

FIG. 18 illustrates a medicinal inhaler 550 according to anotherembodiment of the present disclosure. By way of example only, theinhaler 550 is substantially the same as the inhaler 250 of FIG. 15 andincludes the flow governor 101 positioned in the air flow path 546 ofthe inhaler, except that the inhaler 550 further includes one or morepressure sensors 525, 527 located in the dedicated flow governor airflow path 514. Reference is made to the description above accompanyingFIG. 15 for a more complete description of the features and elements(and alternatives to such features and elements) of the inhaler 550 ofFIG. 18.

As shown in FIG. 18, a pressure sensor 525 is located in fluidcommunication with the dedicated air flow path 514. The pressure sensor525 is connected to a controller (not shown), both of which are poweredby a suitable power source (not shown) with an appropriate switch toprovide a power on/off function.

Generally, a controller of the present disclosure can be a suitableelectronic device, such as, for example, a programmable logic controller(“PLC”), a programmable circuit board (“PCB”), a microprocessor, and/orother suitable devices or structures. As such, the controller 151 mayinclude both hardware and software components, and the term “controller”is meant to broadly encompass the combination of such components.

With continued reference to FIG. 18, when the power is switched on, thepressure sensor 525 determines the atmospheric pressure. When thepatient inhales air through the inhaler 550, causing air to flow out ofthe air outlet 516, air flows into the air flow path 514 via the airinlet 515, and the pressure sensor 525 detects and/or measures thedynamically changing air pressure brought about by the patient'sinspiratory effort in conjunction with the functionality of the flowgovernor 101.

Detection of pressure changes, relative to the initial atmosphericpressure, via cooperation between the pressure sensor 525 and acontroller, can be used to calculate the air flow rate past the pressuresensor 525. (The air flow rate causes a reduction in local air pressure,via the Bernoulli Effect.) When a desired pre-determined flow rate isreached, an electronic signal can be sent to a suitable component, suchas a Light Emitting Diode (LED) or Liquid Crystal Display (LCD) or audiospeaker, to provide a cue for the user to actuate the inhaler 550.Alternatively, the electronic signal could be used to enable a mechanismto automatically actuate the inhaler 550.

Furthermore, in some embodiments, a second pressure sensor 527 can beincluded in the air flow path 514 towards the air outlet 516. Thepresence of this second pressure sensor 527 can be used to determine airflow direction via comparison (e.g., performed by the controller) of therelative local air pressures at the two pressure sensors 525, 527, whichcan be used to distinguish inspiration from exhalation (e.g., if apatient blows into the inhaler 550 instead of sucking air through theinhaler 550). This can allow a linked breath-actuation triggeringmechanism (e.g., mechanical or electronic) to be arranged not to operateif the patient breathes out into the inhaler, rather than in through it,the two breathing modes being easily differentiated by the differentrelative pressure drop relationships detected by the first and secondsensors 525 and 527.

Inclusion of two pressure sensors 525, 527 in fluid communication withthe air flow path 514 enables measurement (in conjunction with theappropriate electrical components, such as a controller (e.g., aprogrammable circuit board (PCB)), a power source, etc.) of pressurechanges, which can be correlated with air flow rates. When apredetermined flow rate is achieved, this can prompt a signal to triggeran electrical firing mechanism to actuate the inhaler canister 551. Sucha mechanism can negate the requirement for the patient to coordinateinhaling and actuating the inhaler. In addition, the triggering flowrate can be programmed differently for different products.

In each case, though, use of an integral flowmeter (which the pressuresensors 525, 527 can effectively be) and electronic actuation can ensurethat the inhaler 550 can be actuated at an appropriate time in thepatient's inspiratory maneuver. The electronic circuitry involved canalso be configured to allow each triggering event to be counted andrecorded, and can be used to also provide a dose count, e.g. for displayto the patient of the theoretical number of doses thus still remaining.

As well as using the pressure measurements and the calculated flow ratedata to trigger canister actuation, such a system can optionally beconfigured to provide feedback to the patient and to their physician.

The air flow path 514 containing the flow governor 101 can beincorporated, in a similar fashion as already described, into any of thevariety of inhalers mentioned above. It should also be understood thatthe incorporation of pressure sensors in the flow governor air flow pathcan be employed in any inhaler, such as that of any of FIGS. 15-17, orany other inhaler of the present disclosure. By way of example, thepressure sensors of FIG. 18 can be positioned in an air flow path formedin the cap 426 of FIG. 17. The relevant electronic componentry can alsobe incorporated into the cap 426.

In some embodiments, no matter which type of inhaler is employed, theair flow path 514 including the flow governor 101 and the pressuresensors 525, 527, along with the relevant electrical components, can bemanufactured as a separate part or component, or as a portion of theinhaler 550. FIGS. 20-23, described below, illustrate exemplary flowgovernor assemblies (or “air flow paths” or “air flow path assemblies”)of the present disclosure comprising flow governors of the presentdisclosure that can be separately formed and put in fluid communicationwith or otherwise incorporated into an inhaler, or that can form aportion of an inhaler of the present disclosure.

FIG. 19 illustrates an inhaler 750 according to another embodiment ofthe present disclosure, including the flow governor 101 of FIGS. 3-8. Byway of example, the inhaler 750 is illustrated as being a variant of aninhaler available under the trade designation AUTOHALER™ from 3MCompany, St. Paul, Minn. Additional details regarding the inhaler 750can be found in U.S. Pat. No. 7,296,567, which is incorporated herein byreference in its entirety.

As shown in FIG. 19, the flow governor 101 is positioned in a dedicatedair flow path 714 located in a bottom portion of a housing 755 of theinhaler 750, which is integrally formed with the housing 755. Thededicated air flow path 714 includes an air inlet 715 (e.g., defined byan auxiliary open end 720) open to ambience and an air outlet 716 influid communication with an air flow path 746 of the inhaler 750.Particularly, the dedicated air flow path 714 is arranged substantiallyhorizontally, such that the air inlet 715 is located generally below themouthpiece 757. Sealing means (not shown) are provided to ensure thatthere are no significant air leak inlets elsewhere in the inhaler 750,in order that substantially all the air flow through the inhaler 750passes through the dedicated air flow path 714.

In this embodiment, the inspiratory air flow is drawn via the air inlet715 (e.g., via an inlet grill, screen or grate 728) into the flowgovernor 101 and thence into the region around a stem socket 759. Whenthe patient inhales on the mouthpiece 757 of the inhaler 750 (whichdefines an inspiration orifice 745), a vane 777 lifts in the inspiratoryair flow, that lifting triggering a mechanical dose release mechanism728. The emerging medicament formulation spray 761 is entrained in theair flow from the air outlet 709 of the flow governor 101 and the airoutlet 716 of the dedicated air flow path 714 and emerges with the airflow via the mouthpiece 757. It will be noted by one skilled in the artthat flow governors of the present invention may be positioned inmultiple locations in such an inhaler, e.g. at the rear of the inhaler,at the front, on the top, to one side, etc. Additionally, it will beapparent that the outer form of the inhaler can be shaped and styledindependently of the internal air flow surfaces.

Again, incorporation of an appropriate electronic memory device couldallow capture, storage and retrieval of the patient's inhalation profile(flow rates, pressure drops, etc.) corresponding to each time theinhaler was used. Inclusion of a means to transmit the data, e.g. via acable or using wireless technology, to a secondary device, e.g. acomputer or ‘smart’ phone, could make these data readily available tothe patient's physician or others, in order to allow them to monitor thepatient's ability to use the inhaler successfully and to allowappropriate and timely health care advice to be provided based onanalysis and interpretation of the retrieved information.

In alternative embodiments, the breath-actuated inhaler can include botha reusable and a replaceable part. For example, a reusable partcontaining the complex and relatively expensive electronics could bepaired in turn with a series of replaceable medicament containingcartridges.

In such embodiments, the flow governor can be associated with thereplaceable cartridge or, alternatively and preferably, with thereusable unit. In either case, the air flow path of the inhaler can beconfigured to pass through either the reusable part, the replaceablerefill part, or both.

In yet another embodiment, two or more flow governors with differingresistances and/or collapse characteristics can be incorporated into amedicinal inhaler of the present disclosure, or an air flow path of thepresent disclosure for use with a medicinal inhaler, for example, in aparallel flow path configuration. In a still further embodiment, two ormore flow governors with differing resistances and/or collapsecharacteristics can be incorporated into a medicinal inhaler or air flowpath of the present disclosure in a series flow path arrangement. Suchembodiments can provide a greater ability to adjust the flow rate versuspressure drop characteristics of medicinal inhalers.

Flow Governor Assemblies

FIG. 20 illustrates a flow governor assembly (or “air flow path” or “airflow path assembly”) 630 according to one embodiment of the presentdisclosure. The flow governor assembly 630 can be separately formed andput in fluid communication with or otherwise incorporated into aninhaler, or can form a portion of an inhaler of the present disclosure.As shown in FIG. 20, the flow governor assembly 630 can include ahousing 635 that defines an air flow path 614 comprising an air inlet615 and an air outlet 616; a flow governor 101 positioned in an air flowpath 614; and a constriction 623 in the air flow path 614. The housing635 is shown in greater detail in FIG. 21 and described in greaterdetail below.

The flow governor 101 can be configured to provide a variable (dynamic)resistance to air flow in an air flow path 614; and the constriction 623can be configured to provide a fixed (static) resistance to air flow inthe air flow path 614. The constriction 623 can include one or more of aventuri section (as shown), a narrow passageway (e.g., a narrowpassageway, relative to adjacent regions/portions of the air flow path614), a tortuous path, and a combination thereof. A tortuous path caninclude one or more twists, bends or turns (e.g., a sharp turn of atleast 60 degrees).

In addition, in some embodiments, the flow governor assembly 630 canfurther include a first (air inlet) pressure sensor 625, and a second(air outlet) pressure sensor 627. The flow governor assembly 630 can beof dimensions (e.g., a length) appropriate to the physical dimensions ofan associated inhaler.

In some embodiments, the housing 635 can be a separate element that canbe positioned within, positioned in fluid communication with, and/orcoupled to a housing of an inhaler. Additionally, or alternatively, insome embodiments, the housing 635 can refer to a portion of a housing ofan inhaler, such that the housing 635 is integrally formed with ahousing of an inhaler.

The air flow path 614, and particularly, the air inlet 615 can be shapedto improve the sensitivity of at least the first pressure sensor 625.The first pressure sensor 625 is connected to the air flow path 614 by afirst conduit 621. The dimensions of this conduit (e.g., itscross-sectional area) can be chosen to ensure an appropriate balancebetween having a desirably low pressure drop along its length versusavoiding it being open enough to significantly affect the air flow inthe main air flow path 614. In some embodiments, this conduit can beround in cross-section, with an internal diameter of approximately 2 mmand a total internal length of approximately 15 mm.

As mentioned above, the air flow path 614 can further include a fixed orstatic resistance, particularly, in the form of a constriction (or“venturi constriction”) 623 located between the air inlet 615 and theair outlet 616 that particularly forms a venturi tube (or venturisection) that effectively amplifies the local air flow induced pressuredrop at the first pressure sensor 625.

Particularly, the constriction 623 can be located upstream of the flowgovernor 101. Such an amplification can enable the use of a lesssensitive pressure sensor to measure the air flow rate with a givenaccuracy. This helps to constrain the manufacturing cost of the inhalerinto which the assembly 630 is incorporated.

Addition of the second pressure sensor 627 connected by a second conduit629 (e.g., in some embodiments, having an internal diameter ofapproximately 2 mm and an internal length of approximately 9 mm), to theair flow path 614 at a position downstream of, and away from, theventuri section constriction 623 can assist in determining the air flowdirection (i.e., to distinguish inhalation from exhalation). This allowsa linked breath-actuation triggering mechanism (e.g., mechanical orelectronic) to be arranged not to operate if the patient breathes outinto the inhaler, rather than in through it, the two breathing modesbeing easily differentiated by the different relative pressure droprelationships detected by the first and second sensors 625 and 627.

In some embodiments, the first conduit 621 can have a firstcross-sectional area (e.g., an average cross-sectional area, or across-sectional area in a region of the first conduit located adjacentthe first pressure sensor); the second conduit 629 can have a secondcross-sectional area (e.g., an average cross-sectional area, or across-sectional area in a region of the first conduit located adjacentthe first pressure sensor); and the air flow path 614 can have a thirdcross-sectional area (e.g., an average cross-sectional area, or across-sectional area in a region of the first conduit or the secondconduit).

In some embodiments, the ratio of the first cross-sectional area to thethird cross-sectional area and/or the ratio of the secondcross-sectional area to the third cross-sectional area can be no greaterthan 0.3; in some embodiments, no greater than 0.25; in someembodiments, no greater than 0.2; in some embodiments, no greater than0.18; in some embodiments, no greater than 0.16; in some embodiments, nogreater than 0.15; in some embodiments, no greater than 0.1; in someembodiments, no greater than 0.08; in some embodiments, no greater than0.07; and in some embodiments, no greater than 0.05.

The present inventors calculated that, in some embodiments, an inhalercomprising the flow governor assembly 630 of FIG. 20 can provide anoverall resistance to air flow at 20 L/min. (below the collapse flowrate) of around 0.8 Pa^(0.5) min./L. This is a desirable figure for aninhaler for the treatment of either COPD or asthma. Computational FluidDynamics (CFD) is a useful tool for use by one skilled in the art todevelop appropriately modified and dimensioned alternative embodimentsto those shown herein.

In some embodiments, where an inhaler incorporates one or more pressuresensors, the patient's inhalation profile can be recorded for each useof the inhaler. With inclusion of the appropriate electronic components,e.g. a memory device and data transmission means, each inhalationprofile of the patient can be captured, stored and retrieved for futureanalysis and interpretation. This can allow the patient's physician andothers to monitor the patient's ability to use the inhaler successfullyand can allow appropriate and timely health care advice and/orinterventions to be provided.

Furthermore, in some embodiments, air flow pressure drop measurementscan be made to enable an inhaler to register both the fact that a dosewas taken and to record the corresponding inhalation profile. Thisenables the patient's physician, or an authority or organization payingfor the patient's health care provision, to know that the patient hasactually taken the dose. Previous inhalers that have registered therelease of a dose, even with a record of the date and time of thatrelease, have not registered or recorded the corresponding inhalationprofile, making them vulnerable to ‘dose dumping’, a practice in whichpatients can deceive their physicians and others into thinking that theyare taking their prescribed doses even when in fact they are simplywasting them by spraying the doses into the surrounding air, etc. Suchpractices are well known as occurring where patients are embarrassed totell their physician that they have not been following their prescribedtreatment regime. The ability to detect such practices, via utilizationof embodiments of the present disclosure, allows health careprofessionals the opportunity to understand what patients are actuallydoing, and allows them to advise and/or alter treatment regimesaccordingly.

FIG. 21 illustrates one example of the elements or components that canbe used to make the flow governor assembly 630 of FIG. 20. For example,in some embodiments, a controller 632 (e.g., a programmable circuitboard (PCB)) can include the two pressure sensors 625, 627. As shown inFIGS. 20-21, the flow governor 101 comprises the tubular element 102 andthe internal support structure 103. The air flow path 614 can be formedby a housing 635, which is shown as including a front housing 633 and arear housing 634, e.g., for ease of plastic injection molding that canbe coupled together (e.g., via any of the coupling means described abovewith respect to coupling the tubular element 102 and the internalsupport structure 103). In some embodiments, the housing 635 can beformed by two or more longitudinal portions (i.e., as shown in FIG. 21by way of example), or additionally or alternatively, the housing 635can be formed of two or more transverse portions that are joinedtransversely, relative to a longitudinal direction D, i.e., relative tothe general air flow direction. The separate housing 635 is shown forsimplicity and by way of example only; however, it should be understoodthat the assembly 630 and air flow path 614 can instead be formed (e.g.,integrally formed) with a housing of a medicinal inhaler, and theinhaler can be modified to include all of the elements shown in FIGS.20-21 of the assembly 630.

Various parameters affect the exact collapsing air flow rate andgoverning air flow rate for the flow governor 101 and the flow governorassembly 630. Examples of such parameters include the material formingthe tubular element 102; the diameter and thickness of the tubularelement material; the shape and dimensions of the constriction 623 andof the internal support structure 103; and environmental factors such astemperature and humidity (e.g., depending on the tubular elementmaterial). Based on the teachings of the present disclosure, a person ofordinary skill in the art will recognize how to test the effects ofvarying these different input parameters without departing from thespirit and scope of the present invention, in order to optimize an exactconfiguration of flow governor and air flow path for a particularapplication.

FIG. 22 illustrates a flow governor assembly 830 according to anotherembodiment of the present disclosure. The flow governor assembly 830 canbe separately formed and put in fluid communication with or otherwiseincorporated into an inhaler, or can form a portion of an inhaler of thepresent disclosure. As shown in FIG. 22, the flow governor assembly 830can include a flow governor 801 positioned in an air flow path 814, theair flow path 814 including an air inlet 815 and an air outlet 816. Theair flow path 814 can be formed by a housing 835. In some embodiments,the housing 835 can be a separate element that can be positioned within,positioned in fluid communication with, and/or coupled to a housing ofan inhaler. Additionally, or alternatively, in some embodiments, thehousing 835 can refer to a portion of a housing of an inhaler, such thatthe housing 835 is integrally formed with a housing of an inhaler.

The flow governor 801 includes a tubular element 802 and an internalsupport structure 803. As shown in FIG. 22 by way of example only, insome embodiments, the internal support structure 803 can include ahollow base 804 that can be at least partially formed by the housing835, or a portion thereof, such that the tubular element 802 isstretched externally around one portion (e.g., an outer wall) of thehousing 835 and is located internally with respect to another portion ofthe housing 835. In such embodiments, the entire internal supportstructure 803 can be integrally formed, or provided by, a portion of thehousing 835, which, as described above, can also form at least a portionof an inhaler.

As further shown in FIG. 22, the air flow path 814 can include (e.g.,the housing 835 can include) one or more inwardly-projecting protrusionsor features 837 positioned at one or more desired longitudinal positionsto encourage the tubular element 802 of the flow governor 801 tocollapse at specific, pre-defined locations. In some embodiments, theone or inwardly-projecting protrusions 837 can be in the form ofpinching splines, or in some embodiments, the protrusion(s) 837 caninclude an annular protrusion surrounding the tubular element 802. Theprotrusions(s) 837 can apply mechanical stress to the tubular element802. By altering the size and/or number of the protrusion(s) 837, theflow rate at which the tubular element 802 collapses can be controlled.Additionally, or alternatively, in some embodiments, the tubular elementmaterial properties can be controlled to encourage precise collapsegeometry and characteristics, e.g., by employing a particular Shorehardness at a specific section of the tubular element 802.

The protrusion(s) 837 can also reduce any tendency of the inwardlyflexing regions of the tubular element 802 to stick to the housing 835,e.g. if the patient exhales moisture into the inhaler.

Furthermore, in some embodiments, the air flow path 814 can include aconstriction, and particularly, a constriction located upstream of theflow governor 801, i.e., toward the air inlet 815, used as a venturisection to accelerate the local air velocity past an adjacent pressuresensor (not shown), as described above with respect to FIGS. 20 and 21.Such an arrangement can allow for more precise pressure measurements(and calculated air flow rate measurements) than would otherwise beachieved from a given pressure sensor.

FIG. 23 illustrates a flow governor assembly 930 according to anotherembodiment of the present disclosure. The flow governor assembly 930 canbe separately formed and put in fluid communication with or otherwiseincorporated into an inhaler, or can form a portion of an inhaler of thepresent disclosure. As shown in FIG. 23, the flow governor assembly 930can include a flow governor 901 positioned in an air flow path 914, theair flow path 914 including an air inlet 915 and an air outlet 916. Theair flow path 914 can be formed by a housing 935. In some embodiments,the housing 935 can be a separate element that can be positioned within,positioned in fluid communication with, and/or coupled to a housing ofan inhaler. Additionally, or alternatively, in some embodiments, thehousing 935 can refer to a portion of a housing of an inhaler, such thatthe housing 935 is integrally formed with a housing of an inhaler.

The flow governor 901 includes a tubular element 902 and an internalsupport structure 903. As shown in FIG. 23 by way of example only, insome embodiments, the internal support structure 903 can include ahollow base 904 that can be at least partially formed by the housing935, or a portion thereof, such that the tubular element 902 isstretched externally around one portion of the housing 935 and islocated internally with respect to another portion of the housing 935.As shown, in some embodiments, the air flow path 914 can include aventuri constriction 923 upstream of the flow governor 901, which can beused to enhance the sensitivity of an adjacent pressure sensor (notshown) as has already been described.

In some embodiments, as shown in FIG. 23, the air flow path 914 caninclude one or more features that can be directly formed in the housing935 into which the flow governor 901 sits to direct the flowing air intothe flow governor 901. For example, as shown in FIG. 23, the air flowpath 914 can include a channeling step 936 that directs the air flowinto the flow governor 901 and prevents air flow to an outer, external,side of the tubular element 902, thus preventing pressure drop loss andkeeping the air on the outer surface of the tubular element 902stagnant.

Each embodiment shown in the figures is illustrated as a separateembodiment for clarity in illustrating a variety of features of the flowgovernors and medicinal inhalers of the present disclosure. However, itshould be understood that any combination of elements and features ofany of the embodiments illustrated in the figures and described hereincan be employed in the flow governors and medicinal inhalers of thepresent disclosure. For example, any of the features of the flowgovernor assemblies of FIGS. 20-23, or combinations thereof, or partialcombinations thereof, can be incorporated into any of the medicinalinhalers of FIGS. 15-19. Furthermore, any of the flow governor featuresof FIGS. 3-14, or combinations thereof, or partial combinations thereof,can be incorporated into any of the flow governor assemblies ormedicinal inhalers of the present disclosure.

The following embodiments are intended to be illustrative of the presentdisclosure and not limiting.

Embodiments

1. A flow governor for use in a medicinal inhaler, the flow governorcomprising:

a tubular element that defines at least a portion of an air flow path,the tubular element comprising at least one flexible wall configured toflex inwardly in response to an air flow in the air flow path; and

an internal support structure, located within the tubular element andconfigured to preserve at least a predetermined cross-sectional area ofthe air flow path within the tubular element when the at least oneflexible wall of the tubular element flexes inwardly.

2. The flow governor of embodiment 1, wherein the flow governor issubstantially linear.

3. The flow governor of embodiment 1 or 2, wherein the tubular elementis substantially bistable between an uncollapsed state and a collapsedstate.

4. The flow governor of any of embodiments 1-3, wherein the internalsupport structure is rigid relative to the tubular element, and thetubular element is flexible relative to the internal support structure.

5. The flow governor of any of embodiments 1-4, further comprising alongitudinal direction, wherein the at least one flexible wall of thetubular element is oriented substantially parallel to the longitudinaldirection.

6. The flow governor of embodiment 5, wherein the tubular element iselongated along in the longitudinal direction.

7. The flow governor of any of embodiments 1-6, further comprising:

an air inlet located at a first end of the tubular element; and

an air outlet located at a second end, opposite the first end, of thetubular element.

8. The flow governor of any of embodiments 1-7, wherein the flowgovernor has an elliptical transverse cross-sectional shape.

9. The flow governor of any of embodiments 1-8, wherein the tubularelement has an elliptical transverse cross-sectional shape.

10. The flow governor of any of embodiments 1-9, wherein the internalsupport structure has a base having an outer wall, and wherein an end ofthe tubular element is stretched over the outer wall of the base of theinternal support structure.

11. The flow governor of embodiment 10, wherein the outer wall of thebase of the internal support structure has an elliptical transversecross-sectional shape.

12. The flow governor of embodiment 10 or 11, wherein the outer wall ofthe base of the internal support structure has a circular transversecross-sectional shape.

13. The flow governor of any of embodiments 1-12, wherein the internalsupport structure includes at least one hollow pillar, and wherein theair flow path through the flow governor includes a space between anouter wall of the internal support structure and the tubular element,and a space within the at least one hollow pillar.

14. The flow governor of any of embodiments 1-13, wherein the internalsupport structure has a generally H-shaped transverse cross-sectionalshape.

15. The flow governor of any of embodiments 1-14, wherein the internalsupport structure has a generally H-shaped longitudinal cross-sectionalshape.

16. The flow governor of any of embodiments 1-15, wherein the internalsupport structure includes a transverse cross-sectional shape comprisingat least one capital English letter “E”.

17. The flow governor of any of embodiments 1-16, wherein the internalsupport structure includes a transverse cross-sectional shape comprisingat least one of the capital English letters selected from B, C, D, E, H,M, N, O, S, V, W, X and Z.

18. The flow governor of any of embodiments 1-17, wherein the internalsupport structure includes at least one pillar oriented substantiallyalong a longitudinal direction of the tubular element and protrudingfrom an inlet end of the tubular element.

19. The flow governor of any of embodiments 1-18, wherein the internalsupport structure includes at least one hollow pillar defining a lumentherein.

20. The flow governor of any of embodiments 1-19, wherein the internalsupport structure includes at least one solid pillar.

21. The flow governor of any of embodiments 1-20, wherein the internalsupport structure includes two pillars oriented substantially parallelto a longitudinal direction of the tubular element, and a cross memberpositioned to couple the two pillars, the cross member oriented at anon-zero angle with respect to the longitudinal direction.

22. The flow governor of any of embodiments 1-21, wherein the internalsupport structure includes two hollow pillars oriented substantiallyparallel to a longitudinal direction of the tubular element, each pillardefining a lumen therein, and a solid cross member positioned to couplethe two hollow pillars, the cross member oriented at a non-zero anglewith respect to the longitudinal direction.

23. The flow governor of any of embodiments 1-21, wherein the internalsupport structure includes two solid pillars oriented substantiallyparallel to a longitudinal direction of the tubular element, and a solidcross member positioned to couple the two solid pillars, the crossmember oriented at a non-zero angle with respect to the longitudinaldirection.

24. The flow governor of any of embodiments 21, 22 and 23, wherein theinternal support structure includes at least one transverse protrusionextending from the cross member.

25. The flow governor of any of embodiments 21-24, wherein the crossmember is oriented substantially perpendicularly with respect to thelongitudinal direction.

26. The flow governor of any of embodiments 1-25, wherein the internalsupport structure includes at least one rib that protrudes substantiallyorthogonally with respect to the at least one flexible wall of thetubular element.

27. A medicinal inhaler comprising at least one flow governor of any ofthe preceding embodiments positioned in fluid communication with an airflow path of the medicinal inhaler.

28. The medicinal inhaler of embodiment 27, wherein the medicinalinhaler includes at least two flow governors arranged in parallel.

29. The medicinal inhaler of embodiment 27 or 28, wherein the medicinalinhaler includes at least two flow governors arranged in series.

30. A medicinal inhaler comprising:

a housing comprising

-   -   a tubular sleeve portion dimensioned to receive a canister        comprising a medicament, and    -   a patient port;

an air flow path including an air inlet and an air outlet, wherein theair outlet is defined by the patient port; and

the flow governor of any of embodiments 1-26 positioned in the air flowpath.

31. The medicinal inhaler of any of embodiments 27-30, wherein themedicinal inhaler is a pressurized metered dose inhaler (pMDI).

32. The medicinal inhaler of any of embodiments 27-30, wherein themedicinal inhaler is at least one of a breath-actuated inhaler, apressurized metered dose inhaler (pMDI), a dry powder inhaler (DPI), anebulizer, and a combination thereof.

33. The medicinal inhaler of any of embodiments 30-32, wherein thetubular sleeve portion of the housing includes a first open end, andwherein the housing further includes a second open end dimensioned toreceive the flow governor.

34. The medicinal inhaler of embodiment 33, wherein the housing furtherincludes a cover or a seal positioned to seal the first open end fromambience.

35. The medicinal inhaler of any of embodiments 27-34, wherein the flowgovernor is positioned in a dedicated air flow path, wherein thededicated air flow path includes an air inlet open to ambience and anair outlet in fluid communication with the air flow path of the inhaler,and wherein the flow governor is positioned between the air inlet andthe air outlet of the dedicated air flow path.

36. The medicinal inhaler of embodiment 35, wherein the dedicated airflow path is integrally formed with the housing.

37. The medicinal inhaler of embodiment 35, or 36, wherein the dedicatedair flow path is formed in a rear portion of the housing, opposite thepatient port.

38. The medicinal inhaler of embodiment 35 or 36, wherein the dedicatedair flow path is formed in a bottom portion of the housing.

39. The medicinal inhaler of embodiment 38, wherein the air inlet of thededicated air flow path is located below the patient port.

40. The medicinal inhaler of any of embodiments 30-39, furthercomprising a cover positioned over the tubular sleeve portion of thehousing to seal the open end from ambience, such that any air taken intothe inhaler is moved through the flow governor.

41. The medicinal inhaler of any of embodiments 30-40, furthercomprising a skirt seal located between an outer surface of the canisterand an inner surface of the housing.

42. The medicinal inhaler of any of embodiments 30-41, furthercomprising a cap configured to be coupled to the tubular sleeve portionof the housing to seal the tubular sleeve portion, the cap defining theair inlet and including the flow governor.

43. The medicinal inhaler of any of embodiments 27-42, furthercomprising a pressure sensor located in the air flow path upstream ofthe flow governor.

44. The medicinal inhaler of any of embodiments 27-43, furthercomprising a first pressure sensor located in the air flow path upstreamof the flow governor and a second pressure sensor located in the airflow path downstream of the flow governor.

45. A flow governor assembly for use in a medicinal inhaler, the flowgovernor assembly comprising:

a housing;

an air flow path defined by the housing and including an air inlet andan air outlet; and

the flow governor of any of embodiments 1-26, the flow governor beingpositioned in the air flow path between the air inlet and the airoutlet.

46. The flow governor assembly of embodiment 45, further comprising afirst pressure sensor positioned in fluid communication with the airflow path upstream of the flow governor and a second pressure sensorpositioned in fluid communication with the air flow path downstream ofthe flow governor.

47. The flow governor assembly of embodiment 45 or 46, furthercomprising a first pressure sensor located in a first conduit connectedto the air flow path upstream of the flow governor and a second pressuresensor located in a second conduit connected to the air flow pathdownstream of the flow governor.

48. The air flow path of embodiment 47, further comprising aconstriction located in the air flow path adjacent where the firstconduit connects to the air flow path.

49. The air flow path of any of embodiments 45-48, further comprising aconstriction located between the air inlet and the flow governor.

50. A method of using a medicinal inhaler, the method comprising:

-   -   providing a medicinal inhaler comprising a flow governor        according to any of embodiments 1-26; and

varying an air flow resistance of the inhaler in response to air flow inthe air flow path of the flow governor.

51. The method of embodiment 50, further comprising inserting a patientport of the medicinal inhaler into a body cavity of a patient; andinhaling through the patient port to cause air flow in the air flow pathof the flow governor.

52. The method of embodiment 50 or 51, wherein varying the air flowresistance of the inhaler includes flexing the at least one tubular wallinwardly toward the internal support structure.

It is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the above description or illustrated in theaccompanying drawings. The invention is capable of other embodiments andof being practiced or of being carried out in various ways. Also, it isto be understood that the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. It isto be further understood that other embodiments may be utilized, andstructural or logical changes may be made without departing from thescope of the present disclosure.

The following prophetic examples are intended to be illustrative of thepresent disclosure and not limiting.

EXAMPLES Example 1—Governing Flow Rate

FIG. 24 and Table 1 show the calculated range of flowrates that patientswill inhale through flow governor assemblies having the configuration ofthe flow governor assembly 630 of FIGS. 20 and 21, comprising the flowgovernor 101 of FIGS. 3-8, with nominal flow governing values of 30, 40and 50 L/min., respectively. It is clear from FIG. 24 and Table 1 thatthe spread in flow rates is greater for the higher flow governor nominalgoverning flow rates.

For modeling purposes, a normal distribution of governing flowrates hasbeen taken around each target governing volumetric flow rate (i.e., 30L/min., 40 L/min. and 50 L/min.), and the below spreads of datarepresent the distributions of flow rates at which the flow governorswill operate within a population of flow governor assemblies. Forexample, for the case of a target governing volumetric flow rate of 30L/min., a small number of flow governors will collapse at around 25L/min, whereas most would be expected to govern at a flow rate close tothe target of 30 L/min, and a small number will govern at a flow rateclose to 35 L/min. It is assumed that if a flow governor collapses, thenthe resistance to flow will increase significantly and the pressure dropwill be dominated by the dynamic, or variable, resistance.

The below data were calculated by modeling the pressure drop at variousflow rates using the following equation:

Pressure drop(Pa)=((R ² +D ²)×F ²)/1000

where: R=Static resistance, Pa^(0.5)(min./L)

D=Dynamic resistance, Pa^(0.5)(min./L)

F=Flow rate, L/min

The static resistance of the flow governor assembly 630 was estimated tobe 0.83 Pa^(0.5)(min./L), based on a combination of the resistance fromthe inlet losses, venturi resistance, the resistance of the flowgovernor, and the outlet losses.

TABLE 1 Ranges of flowrates with governing flow rates of 30, 40 and 50L/min. Nominal governing Flow rate when Flow rate when flow rateinhaling at 0.5 kPa inhaling at 4 kPa 30 L/min. 25 L/min. 35 L/min. 40L/min. 27 L/min. 45 L/min. 50 L/min. 27 L/min. 55 L/min.

The inventors have found particular advantages with flow governors ofthis configuration having a nominal governing flow rate of 30 L/min.

Example 2—Air Flow Resistance

Another important parameter that can be optimized is the static air flowresistance of the assembly.

A flow governor assembly having the configuration of the flow governorassembly 630 of FIGS. 20-21, comprising the flow governor 101 of FIGS.3-8 was formed having a static resistance of 0.83 Pa^(0.5)(min./L) and anominal governing flow rate of 30 L/min. The performance of such a flowgovernor assembly is illustrated by the solid trace in FIG. 25, derivedfrom data calculated using the equation described above in Example 1. Asshown, this design of flow governor assembly will allow a patient whoinhales with a pressure drop of only 0.5 kPa to inhale through theassembly at 25 L/min. The other extreme is a patient who creates apressure drop of 4 kPa, and in this circumstance the inhalation flowrate will be governed according to the tolerance of the flow governor tobetween approximately 25 and 35 L/min. As is clear from the solid trace,this design ensures that all medications will be delivered within thisflow rate range of approximately 25 to 35 L/min., independent of patientlung capacity. This will substantially improve dose consistency forpatients (e.g., COPD patients), both inter-patient and intra-patient.All patients will thus benefit from such a flow governor assembly.

The dashed trace in FIG. 25 shows the effect of a higher staticresistance for the assembly, of 1.0 Pa^(0.5) min./L. Some patients,particularly those who inhale with a pressure drop of only around 0.5kPa, will not achieve the flow rate required for the flow governor tooperate. These patients will not benefit directly from the flowgovernor.

The dotted trace in FIG. 25 shows the effect of a lower staticresistance for the flow governor assembly, of 0.6 Pa^(0.5) min./L. Allpatients will find it easier to inhale through the assembly and someweaker patients will find it easier to obtain a flow rate close to thegoverning flow rate. However, too low a static resistance can lead toincreased drug deposition in the mouth and the throat, which isundesirable, so it is also preferable to avoid the static resistancebeing too low.

TABLE 2 Flow rate when Flow rate when Characteristics inhaling at 0.5kPa inhaling at 4 kPa 30 L/min. flow governor; 28 L/min. 35 L/min. 0.6Pa^(0.5) min./L static resistance 30 L/min. flow governor; 25 L/min. 35L/min. 0.8 Pa^(0.5) min./L static resistance 30 L/min. flow governor; 22L/min. 34 L/min. 1.0 Pa^(0.5) min./L static resistance

On the basis of these calculations and these considerations, the idealstatic resistance for the flow governor assembly of FIGS. 20-21comprising the flow governor of FIGS. 3-8 with a governing flow rate of30 L/min. is considered to be around 0.8 Pa^(0.5) min./L. At thisresistance, practically all COPD and asthma patients would be expectedto inhale at a flowrate above about 30 L/min. A higher resistance (e.g.1.0-1.1 Pa^(0.5) min./L) assembly, would result in some COPD patientsnot being able to reach an inhalation rate of 30 L/min.

Typically, only 95% of COPD patients produce an inhalation pressure dropof greater than 0.6 kPa. As a result, provision of flow governorassemblies (and/or inhalers) comprising the flow governors of thepresent disclosure caters satisfactorily for the vast majority of asthmaand COPD patients, who can produce an inhalation pressure drop ofbetween 0.5 and 4.0 kPa.

The embodiments described above and illustrated in the figures arepresented by way of example only and are not intended as a limitationupon the concepts and principles of the present disclosure. As such, itwill be appreciated by one having ordinary skill in the art that variouschanges in the elements and their configuration and arrangement arepossible without departing from the spirit and scope of the presentdisclosure.

All references and publications cited herein are expressly incorporatedherein by reference in their entirety into this disclosure.

Various features and aspects of the present disclosure are set forth inthe following claims.

1. A flow governor for use in a medicinal inhaler, the flow governorcomprising: a tubular element that defines at least a portion of an airflow path, the tubular element comprising at least one flexible wallconfigured to flex inwardly in response to an air flow in the air flowpath; and an internal support structure, located within the tubularelement and configured to preserve at least a predeterminedcross-sectional area of the air flow path within the tubular elementwhen the at least one flexible wall of the tubular element flexesinwardly.
 2. The flow governor of claim 1, wherein the tubular elementis substantially bistable between an uncollapsed state and a collapsedstate.
 3. The flow governor of claim 1, wherein the internal supportstructure is rigid relative to the tubular element, and the tubularelement is flexible relative to the internal support structure.
 4. Theflow governor of claim 1, wherein the internal support structure has abase having an outer wall, and wherein an end of the tubular element isstretched over the outer wall of the base of the internal supportstructure.
 5. The flow governor of claim 1, wherein the internal supportstructure includes at least one hollow pillar, and wherein the air flowpath through the flow governor includes a space between an outer wall ofthe internal support structure and the tubular element, and a spacewithin the at least one hollow pillar.
 6. The flow governor of claim 1,wherein the internal support structure includes a transversecross-sectional shape comprising at least one of the capital Englishletters selected from B, C, D, E, H, M, N, O, S, V, W, X and Z.
 7. Theflow governor of claim 1, wherein the internal support structureincludes at least one hollow pillar defining a lumen therein.
 8. Theflow governor of claim 1, wherein the internal support structureincludes at least one solid pillar.
 9. The flow governor of claim 1,wherein the internal support structure includes two pillars orientedsubstantially parallel to a longitudinal direction of the tubularelement, and a cross member positioned to couple the two pillars, thecross member oriented at a non-zero angle with respect to thelongitudinal direction.
 10. The flow governor of claim 1, wherein theinternal support structure includes two hollow pillars orientedsubstantially parallel to a longitudinal direction of the tubularelement, each pillar defining a lumen therein, and a solid cross memberpositioned to couple the two hollow pillars, the cross member orientedat a non-zero angle with respect to the longitudinal direction.
 11. Theflow governor of claim 1, wherein the internal support structureincludes two solid pillars oriented substantially parallel to alongitudinal direction of the tubular element, and a solid cross memberpositioned to couple the two solid pillars, the cross member oriented ata non-zero angle with respect to the longitudinal direction. 12-15.(canceled)
 16. The flow governor of claim 1, wherein the internalsupport structure includes at least one rib that protrudes substantiallyorthogonally with respect to the at least one flexible wall of thetubular element.
 17. A medicinal inhaler comprising at least one flowgovernor of claim 1 positioned in fluid communication with an air flowpath of the medicinal inhaler.
 18. The medicinal inhaler of claim 17,wherein the medicinal inhaler includes at least two flow governorsarranged in parallel.
 19. The medicinal inhaler of claim 17, wherein themedicinal inhaler includes at least two flow governors arranged inseries.
 20. A medicinal inhaler comprising: a housing comprising atubular sleeve portion dimensioned to receive a canister comprising amedicament, and a patient port; an air flow path including an air inletand an air outlet, wherein the air outlet is defined by the patientport; and the flow governor of claim 1 positioned in the air flow path.21. The medicinal inhaler of claim 17, wherein the medicinal inhaler isa pressurized metered dose inhaler (pMDI).
 22. The medicinal inhaler ofclaim 17, wherein the flow governor is positioned in a dedicated airflow path, wherein the dedicated air flow path includes an air inletopen to ambience and an air outlet in fluid communication with the airflow path of the inhaler, and wherein the flow governor is positionedbetween the air inlet and the air outlet of the dedicated air flow path.23-24. (canceled)
 25. The medicinal inhaler of claim 17, furthercomprising a pressure sensor located in the air flow path upstream ofthe flow governor.
 26. (canceled)